WIPF1 (WAS/WASL-interacting protein family member 1): A Comprehensive Research Report

Introduction

WIPF1 (WAS/WASL-interacting protein family member 1), also known as WIP (WASP-interacting protein), is a proline-rich scaffolding protein that serves as a critical regulator of actin cytoskeleton dynamics in hematopoietic cells. First identified in 1997 by Ramesh and colleagues through a yeast two-hybrid screen designed to find binding partners of the Wiskott-Aldrich syndrome protein (WASP), WIP has emerged as a multifunctional protein essential for proper immune cell function, actin polymerization, and cellular motility [ramesh-1997-wip-discovery-abstract]. The protein is encoded by the WIPF1 gene (with synonyms WASPIP and WIP) and belongs to the evolutionarily conserved verprolin protein family, with orthologs found in organisms ranging from yeast (Vrp1p) to humans [munn-2009-verprolin-review-abstract].

WIP functions primarily as a chaperone and stabilizer of WASP, protecting it from degradation while also acting as a regulator of its actin polymerization activity. Beyond its WASP-dependent roles, WIP exhibits autonomous functions in actin cytoskeleton remodeling and serves as a hub for multiple signaling pathways through its extensive proline-rich sequences. The protein is intrinsically disordered, consisting of consecutive small functional domains and motifs that mediate interactions with a diverse array of cellular partners [sokolik-2020-wip-structure-abstract]. This structural flexibility enables WIP to function as a versatile adapter that integrates multiple signaling inputs to regulate actin-dependent cellular processes, including immune synapse formation, cell migration, phagocytosis, and pathogen subversion.

Domain Architecture and Structural Features

WIP is a 503-amino acid polypeptide characterized by its intrinsically disordered nature, with over 30% of its primary sequence consisting of proline residues [sokolik-2020-wip-structure-abstract]. The protein architecture can be divided into three major functional segments: an N-terminal actin-binding domain, a central proline-rich region that binds SH3 domain-containing proteins, and a C-terminal WASP-binding domain.

The N-terminal region contains actin-binding motifs (ABMs) that directly interact with actin monomers. Structural studies using NMR spectroscopy have revealed that this domain, while largely disordered in its unbound state, contains regions with transient helical and beta-strand character that become ordered upon actin binding [elazari-shalom-2015-abstract]. The actin-binding function is mediated primarily through WH2 (WASP Homology 2) domains, which are approximately 35-residue motifs that bind actin monomers with high affinity [paunola-2002-wh2-review-abstract]. Importantly, functional studies in yeast demonstrated that the WH2 domain is essential for WIP's ability to complement verprolin-deficient cells, underscoring its critical role in cytoskeletal function [vaduva-1999-wip-yeast-abstract].

The central region of WIP is dominated by proline-rich sequences that serve as binding sites for SH3 domain-containing proteins. Antón and colleagues identified that WIP binds to the adaptor protein Nck through its second SH3 domain, with the binding site localized to amino acids 321-415 of WIP [anton-1998-wip-nck-abstract]. This region is distinct from the WASP-binding site, allowing WIP to simultaneously engage both partners and potentially recruit Nck to sites of actin polymerization via the WASP-WIP complex.

The C-terminal domain (approximately residues 416-503) mediates the critical interaction with WASP/N-WASP. NMR structural analysis of the N-WASP EVH1 domain-WIP complex revealed a novel recognition mechanism whereby a 25-residue WIP motif wraps around the EVH1 domain, contacting a narrow but extended surface [volkman-2002-evh1-wip-structure-abstract]. Zettl and Way further characterized the binding motif, identifying the sequence ESRFYFHPISD as the core WH1 binding motif in WIP, with the two conserved phenylalanine residues being critical for the interaction [zettl-2002-wh1-evh1-abstract]. The C-terminal domain of WIP also contains transient secondary structure, including propensity for helical conformation in residues 446-456 and an extended conformation followed by a short helix in residues 468-478 [haba-2013-abstract].

Molecular Function: WASP Stabilization and Regulation

The primary molecular function of WIP is its role as a chaperone and stabilizer of WASP. Studies by Konno and colleagues definitively demonstrated that WASP expression depends on WIP co-expression; WASP gene transfer results in high WASP expression only when WIP is concomitantly present, and WIP-knockdown T cells show concordant reduction of WASP levels [konno-2007-wasp-wip-expression-abstract]. This stabilization function is essential because, in the absence of WIP, WASP is susceptible to degradation by both calpain-mediated proteolysis and the ubiquitin-proteasome pathway.

The relationship between WIP and WASP is complex and bidirectional. Using triple-color FRET technology, Fried and colleagues demonstrated that WIP and WASP interact through two distinct molecular interfaces [fried-2014-fret-wip-wasp-abstract]. The first interaction occurs between the WASP WH1 domain and the C-terminal domain of WIP, and this interaction depends on the phosphorylation status of WIP, which is phosphorylated by PKC-theta in response to T cell receptor activation. The second interaction occurs between the VCA domain of WASP and the N-terminal domain of WIP, and this interaction requires actin as it is inhibited by latrunculin A.

Importantly, WASP activation involves dissociation of the first (WH1-CTD) interaction while leaving the second (VCA-NTD) interaction intact. This conformational change exposes the ubiquitylation site on WASP, leading to its degradation [fried-2014-fret-wip-wasp-abstract]. This mechanism suggests that the activation and degradation of WASP are delicately balanced and depend on the phosphorylation state of WIP, providing an elegant regulatory mechanism for controlling the duration and intensity of WASP signaling.

Contrary to earlier models suggesting that WIP-WASP dissociation was required for WASP activation, Dong and colleagues demonstrated that the WIP-WASP complex mediates TCR-induced NFAT activation without dissociation [dong-2007-wip-wasp-nfat-abstract]. Their structure-function analysis revealed that the N-terminal region of WIP is highly inhibitory for TCR-mediated transcriptional activation, suggesting that WIP, like WASP, is subject to autoinhibition.

Role in Actin Cytoskeleton Dynamics

WIP functions as a critical regulator of actin polymerization and cytoskeletal remodeling. In the original characterization of WIP, Ramesh and colleagues showed that expression of WIP in human B cells increased polymerized actin content and induced the appearance of actin-containing cerebriform projections on the cell surface [ramesh-1997-wip-discovery-abstract]. This effect required the N-terminal actin-binding motif, as truncation mutants lacking this region failed to induce actin polymerization.

The mechanism by which WIP regulates actin dynamics involves both WASP-dependent and WASP-independent pathways. WIP facilitates the localization of WASP to sites of actin polymerization, serving as a shuttle that brings WASP to areas of active cytoskeletal reorganization [anton-2007-wip-review-abstract]. In Dictyostelium studies, Myers and colleagues demonstrated that WIP (designated WIPa) localizes to sites of new pseudopod protrusion, colocalizes with WASP at the leading edge, and increases F-actin elongation in vivo in a WASP-dependent manner [myers-2006-abstract].

Studies in yeast have provided fundamental insights into WIP/verprolin function. Vaduva and colleagues showed that human WIP can functionally replace yeast verprolin, suppressing the growth defects of VRP1 mutations and restoring cytoskeletal organization and endocytosis [vaduva-1999-wip-yeast-abstract]. This complementation depends on both the WH2 actin-binding domain and a putative profilin-binding domain, highlighting the conservation of WIP function across evolution.

Subcellular Localization and Actin-Rich Structures

WIP localizes to multiple actin-rich structures within cells, reflecting its role in diverse actin-dependent processes. These structures include the immune synapse, filopodia, lamellipodia, stress fibers, podosomes, and invadopodia [anton-2007-wip-review-abstract].

In dendritic cells, Chou and colleagues demonstrated that WIP is essential for podosome formation and architecture [chou-2006-wip-podosomes-abstract]. Podosomes are actin-rich adhesive structures that mediate cell-matrix interactions and local matrix degradation in migrating cells. WIP is required for the formation of actin cores containing WASP and cortactin and for the organization of integrin and integrin-associated proteins in circular arrays, which are specific characteristics of podosome structure. WIP exerts these functions by regulating calpain-mediated cleavage of WASP and by facilitating the localization of WASP to sites of actin polymerization at podosomes.

In cancer cells, WIP has been shown to localize to invadopodia, which are actin-rich membrane protrusions that mediate matrix degradation during tumor invasion. García and colleagues demonstrated that WIP interacts with N-WASP and cortactin and is essential for invadopodium assembly in breast cancer cells [garcia-2016-wip-invadopodia-abstract]. Their work established that WIP functions as a hub for signaling molecule recruitment during invadopodium generation and cancer progression.

Role in T Cell Signaling and Immune Function

WIP plays critical roles in T cell receptor signaling and immune function. The protein is essential for proper T cell activation, chemotaxis, and responsiveness to cytokines. Studies using WIP-deficient mice have revealed both WASP-dependent and WASP-independent roles for WIP in immune cell function.

Janssen and colleagues identified a DOCK8-WIP-WASP complex that links T cell receptors to the actin cytoskeleton [janssen-2016-dock8-wip-wasp-abstract]. WIP bridges DOCK8 (dedicator of cytokinesis 8) to WASP and actin in T cells, and DOCK8's guanine nucleotide exchange factor activity is essential for TCR-driven WASP activation, F-actin assembly, and immune synapse formation. This discovery provided an explanation for the overlapping clinical phenotypes of Wiskott-Aldrich syndrome and DOCK8 deficiency.

Le Bras and colleagues investigated the WASP-independent functions of WIP by comparing WIP/WASP double knockout mice to WASP single knockout mice [lebras-2009-wip-il2-abstract]. They found that WIP is essential for IL-2 signaling and responsiveness in T cells. Double knockout T cells had defective response to IL-2, evidenced by failure to phosphorylate STAT5 and induce expression of STAT5-dependent genes. Importantly, these T cells had a disrupted subcortical actin cytoskeleton and impaired actin polymerization after TCR ligation, suggesting that WIP's role in maintaining cytoskeletal integrity underlies its function in IL-2 signaling.

Gallego and colleagues demonstrated that WASP and WIP play complementary roles in T cell homing and chemotaxis [gallego-2005-wip-wasp-chemotaxis-abstract]. T cell homing to spleen and lymph nodes was deficient in WASP-deficient and WIP-deficient mice and severely impaired in double knockout mice. Chemotaxis to SDF-1alpha was significantly impaired in WIP-deficient T cells and severely reduced in double knockout T cells. Their findings indicate that WASP and WIP function downstream of small GTPases and play partially redundant roles in T cell chemotaxis.

In mast cells, Kettner and colleagues demonstrated that WIP regulates signaling via the high-affinity receptor for IgE (FcepsilonRI) [kettner-2004-wip-mast-cells-abstract]. WIP-deficient mast cells showed impaired degranulation, diminished calcium mobilization, and reduced phosphorylation of Syk. WIP was found to associate with Syk after FcepsilonRI ligation and to inhibit Syk degradation, revealing a novel mechanism by which WIP regulates immune receptor signaling.

Role in NK Cell Cytotoxicity

WIP plays an essential role in natural killer (NK) cell function and cytotoxic activity. Krzewski and colleagues identified a multiprotein complex of approximately 1.3 megadaltons consisting of WIP, WASP, actin, and myosin IIA that forms during NK cell activation [krzewski-2006-nk-cell-multiprotein-abstract]. This complex is critical for the cytoskeletal rearrangements required for NK cell-mediated cytolysis.

The assembly of this multiprotein complex is dynamically regulated. WIP and WASP form a constitutive core complex, while actin and myosin IIA are recruited upon NK cell activation. Importantly, inhibitory signaling through killer cell immunoglobulin-like receptors (KIRs) dramatically decreases the recruitment of actin and myosin IIA to the WIP-WASP complex, providing a mechanism by which inhibitory receptors can prevent cytotoxic function [krzewski-2006-nk-cell-multiprotein-abstract]. Notably, actin and myosin IIA can be recruited to WIP even in the absence of WASP, and this recruitment correlates with WIP phosphorylation mediated by PKC-theta.

Further studies demonstrated that WIP is essential for lytic granule polarization and exocytosis in NK cells [krzewski-2008-nk-cell-cytotoxicity-abstract]. Disruption of WIP expression by RNA interference led to almost complete inhibition of cytotoxic activity, establishing WIP as a central regulator of NK cell effector function. The WIP-dependent complex is required for the proper positioning of lytic granules at the immunological synapse, a critical step in target cell killing.

These findings have clinical relevance for Wiskott-Aldrich syndrome, where NK cell dysfunction contributes to increased susceptibility to infections and malignancies. The essential role of WIP in forming the cytoskeletal scaffold required for effective cytotoxicity explains why WIP deficiency results in impaired NK cell function.

Role in Phagocytosis and Macrophage Function

WIP is essential for phagocytosis and macrophage migration, two processes that are critically impaired in Wiskott-Aldrich syndrome. Tsuboi and Meerloo demonstrated that WASP and WIP form a complex at the phagocytic cup, the actin-based membrane structure that macrophages form to engulf foreign particles [tsuboi-2007-phagocytic-cup-abstract]. The WASP-WIP complex is essential for efficient phagocytic cup formation, with WASP phosphorylation on tyrosine 291 playing an important regulatory role. These findings explain the phagocytic defects and recurrent infections observed in WAS patients.

The role of WIP in macrophage chemotaxis was characterized by Tsuboi, who demonstrated that WASP and the mammalian verprolins (WIP, WICH/WIRE) form functional complexes essential for monocyte migration [tsuboi-2006-monocyte-chemotaxis-abstract]. Both WIP and WICH/WIRE are expressed in monocytes and are involved in chemotaxis. When WASP binding to verprolins was blocked, chemotactic migration was impaired in both cell lines and primary human monocytes. Importantly, blocking WASP-verprolin interaction impaired cell polarization but not actin polymerization, indicating that the complex is specifically required for directional migration rather than general cytoskeletal function.

Tsuboi and colleagues further identified formin-binding protein 17 (FBP17) as a critical upstream regulator that recruits WASP, WIP, and dynamin-2 to the plasma membrane [tsuboi-2009-fbp17-abstract]. This recruitment is necessary for the formation of both podosomes and phagocytic cups, representing a common molecular step in these actin-based membrane structures. FBP17 facilitates the simultaneous occurrence of membrane deformation (through its F-BAR domain) and actin polymerization (through WASP-WIP recruitment) at the same membrane sites.

These studies establish that WIP functions in macrophages as part of an integrated system linking membrane dynamics to actin polymerization, enabling the coordinated formation of specialized membrane structures required for immune function.

Additional Protein Interactions: Src Family Kinases

WIP interacts with additional signaling molecules beyond WASP and its core partners. Scott and colleagues used mass spectrometry to identify binding partners for the SH3 domain of Hck, a Src family kinase, and found WIP and WASP among the major interacting proteins in monocytes [scott-2002-hck-wip-abstract]. Using purified proteins, they confirmed that WIP interacts directly with the SH3 domain of Hck. This interaction links WIP to Src family kinase signaling pathways and suggests that WIP may serve as a substrate or regulatory partner for these kinases. The interaction with Hck provides an additional mechanism by which WIP can integrate diverse signaling inputs to regulate actin cytoskeleton dynamics.

Role in Disease: Immunodeficiency and Cancer

Mutations in WIPF1 cause a severe combined immunodeficiency syndrome that resembles Wiskott-Aldrich syndrome. WIP deficiency leads to severe early-onset immunodeficiency in humans and severe autoimmunity and shortened lifespan in mice [alonso-eiras-2024-wip-cancer-abstract]. The clinical phenotype includes features common to WAS, such as thrombocytopenia, recurrent infections, and immunodysregulation, reflecting the essential role of the WIP-WASP complex in hematopoietic cell function [schwinger-2018-abstract].

The importance of WIP in WAS pathology is highlighted by the observation that approximately 80% of identified WAS patients have mutations in the WIP-binding region of WASP, underscoring the clinical significance of the WIP-WASP interaction [chou-2006-wip-podosomes-abstract]. Stewart and colleagues demonstrated that point mutations causing WAS can impair the interaction between WASP and WIP, providing a mechanistic link between disrupted protein interactions and disease [stewart-1999-abstract].

Beyond immunodeficiency, WIP has been implicated in cancer progression. The relationship between WIP and cancer is complex and context-dependent. In solid tumors, overexpression of WIP has been associated with tumor initiation, progression, and dissemination through matrix degradation by invadopodia [alonso-eiras-2024-wip-cancer-abstract]. García and colleagues demonstrated that WIP is necessary for matrix invasion by breast cancer cells and that elevated WIP levels correlate with high invasiveness [garcia-2016-wip-invadopodia-abstract, garcia-2014-abstract].

However, a suppressive function for WIP has been shown in certain hematological cancers. Wang and colleagues identified FLI1 as a direct transcriptional regulator of WIP and showed that depletion of WIP accelerated cell proliferation in leukemia cells, suggesting a tumor suppressor function in this context [wang-2021-abstract]. These data highlight the need for further research to fully understand WIP's diverse functions in different cancer contexts.

Protein-Protein Interactions

WIP serves as a hub for multiple protein-protein interactions, facilitated by its extensive proline-rich sequences and multiple functional domains. Beyond WASP, WIP interacts with numerous signaling proteins including:

Nck adaptor proteins: WIP binds Nck through its second SH3 domain, linking WIP to receptor tyrosine kinase signaling pathways. The presence of profilin in Nck precipitates suggests that Nck may couple extracellular signals to the cytoskeleton via its interaction with WIP and profilin [anton-1998-wip-nck-abstract].

Cortactin: WIP interacts with cortactin, a protein that stabilizes branched actin networks. This interaction is important for invadopodium formation and function [garcia-2016-wip-invadopodia-abstract].

Profilin: WIP contains profilin-binding motifs that link it to actin dynamics, as profilin is a key regulator of actin polymerization [ramesh-1997-wip-discovery-abstract].

Syk kinase: In mast cells, WIP associates with Syk following FcepsilonRI ligation and protects Syk from degradation [kettner-2004-wip-mast-cells-abstract].

DOCK8: WIP bridges DOCK8 to WASP, forming a complex essential for TCR-driven actin assembly [janssen-2016-dock8-wip-wasp-abstract].

Myosin IIA: In NK cells, myosin IIA is recruited to the WIP-WASP complex upon activation. This recruitment is mediated by WIP phosphorylation and is essential for cytotoxic function [krzewski-2006-nk-cell-multiprotein-abstract].

FBP17 (Formin-binding protein 17): FBP17 recruits WIP, WASP, and dynamin-2 to the plasma membrane during podosome and phagocytic cup formation [tsuboi-2009-fbp17-abstract].

Hck kinase: WIP interacts directly with the SH3 domain of Hck, linking WIP to Src family kinase signaling in monocytes [scott-2002-hck-wip-abstract].

Dynamin-2: WIP is recruited together with dynamin-2 by FBP17 to sites of membrane remodeling, connecting WIP to membrane fission machinery [tsuboi-2009-fbp17-abstract].

Evolutionary Conservation and the Verprolin Family

WIP belongs to the verprolin family of proteins, which is evolutionarily conserved from yeast to humans. The yeast ortholog, verprolin (Vrp1p), is an actin- and myosin-interacting protein required for polarized morphogenesis, endocytosis, and cytokinesis [munn-2009-verprolin-review-abstract]. Human WIP can functionally replace verprolin in yeast, demonstrating conservation of function across evolution [vaduva-1999-wip-yeast-abstract].

In mammals, the verprolin family includes three members: WIP (WIPF1), WICH (also known as WIRE; WIPF2), and CR16 (WIPF3). These proteins share conserved actin-binding and WASP-binding domains but have distinct tissue expression patterns and functions. WICH/WIRE interacts preferentially with N-WASP and plays distinct roles in invadopodium maturation compared to WIP [garcia-2016-wip-invadopodia-abstract, kato-2002-abstract].

Open Questions

Several important questions remain regarding WIP function:

1. Regulation of WIP activity: While the regulation of WASP by WIP is well characterized, less is known about how WIP itself is regulated. The autoinhibitory properties of the WIP N-terminus suggest regulatory mechanisms that remain to be fully elucidated.

2. WASP-independent functions: Many studies have focused on WIP's role as a WASP regulator, but WIP clearly has WASP-independent functions. The full scope of these functions and their mechanisms require further investigation.

3. Tissue-specific roles: WIP is expressed in multiple tissues, but most studies have focused on hematopoietic cells. The functions of WIP in other cell types, including neurons and epithelial cells, are less well understood.

4. Cancer context dependency: The opposing roles of WIP in solid tumors versus hematological malignancies require explanation. Understanding the molecular basis for these context-dependent functions could have therapeutic implications.

5. Structural dynamics: As an intrinsically disordered protein, WIP likely undergoes conformational changes upon binding partners. High-resolution structural studies of WIP in complex with its various partners would provide mechanistic insights.

6. Therapeutic potential: Given WIP's role in cancer invasion and immune dysfunction, understanding whether WIP can be targeted therapeutically is of significant interest.

References

• ramesh-1997-wip-discovery-abstract: Ramesh N, Antón IM, Hartwig JH, Geha RS. WIP, a protein associated with Wiskott-Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells. Proc Natl Acad Sci U S A. 1997;94(26):14671-6. DOI: https://doi.org/10.1073/pnas.94.26.14671 PMID: 9405671

• anton-2007-wip-review-abstract: Antón IM, Jones GE, Wandosell F, Geha R, Ramesh N. WASP-interacting protein (WIP): working in polymerisation and much more. Trends Cell Biol. 2007;17(11):555-62. DOI: https://doi.org/10.1016/j.tcb.2007.08.005 PMID: 17949983

• sokolik-2020-wip-structure-abstract: Sokolik CG, Qassem N, Chill JH. The Disordered Cellular Multi-Tasker WIP and Its Protein-Protein Interactions: A Structural View. Biomolecules. 2020;10(7):1084. DOI: https://doi.org/10.3390/biom10071084 PMID: 32708183

• munn-2009-verprolin-review-abstract: Munn AL, Thanabalu T. Verprolin: a cool set of actin-binding sites and some very HOT prolines. IUBMB Life. 2009;61(7):707-12. DOI: https://doi.org/10.1002/iub.195 PMID: 19507265

• volkman-2002-evh1-wip-structure-abstract: Volkman BF, Prehoda KE, Scott JA, Peterson FC, Lim WA. Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome. Cell. 2002;111(4):565-76. DOI: https://doi.org/10.1016/s0092-8674(02)01076-0 PMID: 12437929

• zettl-2002-wh1-evh1-abstract: Zettl M, Way M. The WH1 and EVH1 domains of WASP and Ena/VASP family members bind distinct sequence motifs. Curr Biol. 2002;12(18):1617-22. DOI: https://doi.org/10.1016/s0960-9822(02)01112-0 PMID: 12372256

• konno-2007-wasp-wip-expression-abstract: Konno A, Kirby M, Anderson SA, Schwartzberg PL, Candotti F. The expression of WASP is dependent on WIP. Int Immunol. 2007;19(2):185-92. DOI: https://doi.org/10.1093/intimm/dxl135 PMID: 17205972

• fried-2014-fret-wip-wasp-abstract: Fried S, Reicher B, Pauker MH, et al. Triple-color FRET analysis reveals conformational changes in the WIP-WASp actin-regulating complex. Sci Signal. 2014;7(331):ra60. DOI: https://doi.org/10.1126/scisignal.2005198 PMID: 24962707

• dong-2007-wip-wasp-nfat-abstract: Dong X, Patino-Lopez G, Candotti F, Shaw S. Structure-function analysis of the WIP role in TCR-stimulated NFAT activation. J Biol Chem. 2007;282(41):30303-10. DOI: https://doi.org/10.1074/jbc.M704972200 PMID: 17711847

• janssen-2016-dock8-wip-wasp-abstract: Janssen E, Tohme M, Hedayat M, et al. A DOCK8-WIP-WASp complex links T cell receptors to the actin cytoskeleton. J Clin Invest. 2016;126(10):3837-3851. DOI: https://doi.org/10.1172/JCI85774 PMID: 27599296

• lebras-2009-wip-il2-abstract: Le Bras S, Massaad M, Koduru S, Kumar L, Oyoshi MK, Hartwig J, Geha RS. WIP is critical for T cell responsiveness to IL-2. Proc Natl Acad Sci U S A. 2009;106(18):7519-24. DOI: https://doi.org/10.1073/pnas.0806410106 PMID: 19359486

• gallego-2005-wip-wasp-chemotaxis-abstract: Gallego MD, de la Fuente MA, Anton IM, Snapper S, Fuhlbrigge R, Geha RS. WIP and WASP play complementary roles in T cell homing and chemotaxis to SDF-1alpha. Int Immunol. 2005;18(2):221-32. DOI: https://doi.org/10.1093/intimm/dxh310 PMID: 16141245

• kettner-2004-wip-mast-cells-abstract: Kettner A, Kumar L, Antón IM, et al. WIP regulates signaling via the high affinity receptor for immunoglobulin E in mast cells. J Exp Med. 2004;199(3):357-68. DOI: https://doi.org/10.1084/jem.20030652 PMID: 14757742

• vaduva-1999-wip-yeast-abstract: Vaduva G, Martinez-Quiles N, Anton IM, et al. The human WASP-interacting protein, WIP, activates the cell polarity pathway in yeast. J Biol Chem. 1999;274(24):17103-8. DOI: https://doi.org/10.1074/jbc.274.24.17103 PMID: 10358064

• chou-2006-wip-podosomes-abstract: Chou HC, Antón IM, Holt MR, et al. WIP regulates the stability and localization of WASP to podosomes in migrating dendritic cells. Curr Biol. 2006;16(23):2337-44. DOI: https://doi.org/10.1016/j.cub.2006.10.037 PMID: 17141616

• garcia-2016-wip-invadopodia-abstract: García E, Ragazzini C, Yu X, et al. WIP and WICH/WIRE co-ordinately control invadopodium formation and maturation in human breast cancer cell invasion. Sci Rep. 2016;6:23590. DOI: https://doi.org/10.1038/srep23590 PMID: 27009365

• alonso-eiras-2024-wip-cancer-abstract: Alonso-Eiras J, Anton IM. Multifaceted role of the actin-binding protein WIP: Promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken). 2024;82(3):186-196. DOI: https://doi.org/10.1002/cm.21935 PMID: 39329352

• paunola-2002-wh2-review-abstract: Paunola E, Mattila PK, Lappalainen P. WH2 domain: a small, versatile adapter for actin monomers. FEBS Lett. 2002;513(1):92-7. DOI: https://doi.org/10.1016/s0014-5793(01)03242-2 PMID: 11911886

• anton-1998-wip-nck-abstract: Antón IM, Lu W, Mayer BJ, Ramesh N, Geha RS. The WIP binds to the adaptor protein Nck. J Biol Chem. 1998;273(33):20992-5. DOI: https://doi.org/10.1074/jbc.273.33.20992 PMID: 9694849

• noy-2012-wip-review-abstract: Noy E, Fried S, Matalon O, Barda-Saad M. WIP remodeling actin behind the scenes: how WIP reshapes immune and other functions. Int J Mol Sci. 2012;13(6):7629-7647. DOI: https://doi.org/10.3390/ijms13067629 PMID: 22837718

• garcia-2014-abstract: García E, Machesky LM, Jones GE, Antón IM. WIP is necessary for matrix invasion by breast cancer cells. Eur J Cell Biol. 2014;93(10-12):413-23. DOI: https://doi.org/10.1016/j.ejcb.2014.07.008 PMID: 25169059

• ramesh-2009-wasp-wip-advances-abstract: Ramesh N, Geha R. Recent advances in the biology of WASP and WIP. Immunol Res. 2009;44(1-3):99-111. DOI: https://doi.org/10.1007/s12026-008-8086-1 PMID: 19018480

• schwinger-2018-abstract: Schwinger W, Urban C, Ulreich R, et al. The Phenotype and Treatment of WIP Deficiency: Literature Synopsis and Review of a Patient. Front Immunol. 2018;9:2554. DOI: https://doi.org/10.3389/fimmu.2018.02554 PMID: 30450104

• wang-2021-abstract: Wang C, Sample KM, Gajendran B, et al. FLI1 Induces Megakaryopoiesis Gene Expression Through WAS/WIP-Dependent and Independent Mechanisms. Front Immunol. 2021;12:607836. DOI: https://doi.org/10.3389/fimmu.2021.607836 PMID: 33717090

• stewart-1999-abstract: Stewart DM, Tian L, Nelson DL. Mutations that cause the Wiskott-Aldrich syndrome impair the interaction of WASP with WIP. J Immunol. 1999;162(8):5019-24. PMID: 10202051

• haba-2013-abstract: Haba NY, Gross R, Novacek J, et al. NMR determines transient structure and dynamics in the disordered C-terminal domain of WIP. Biophys J. 2013;105(2):481-93. DOI: https://doi.org/10.1016/j.bpj.2013.05.046 PMID: 23870269

• elazari-shalom-2015-abstract: Elazari-Shalom H, Shaked H, Esteban-Martin S, Salvatella X, Barda-Saad M, Chill JH. New insights into the role of the disordered WIP N-terminal domain. FEBS J. 2015;282(4):700-14. DOI: https://doi.org/10.1111/febs.13174 PMID: 25495558

• myers-2006-abstract: Myers SA, Leeper LR, Chung CY. WASP-interacting protein is important for actin filament elongation and prompt pseudopod formation in response to a dynamic chemoattractant gradient. Mol Biol Cell. 2006;17(10):4564-75. DOI: https://doi.org/10.1091/mbc.e05-10-0994 PMID: 16899512

• kato-2002-abstract: Kato M, Miki H, Kurita S, et al. WICH, a novel verprolin homology domain-containing protein that functions cooperatively with N-WASP in actin-microspike formation. Biochem Biophys Res Commun. 2002;291(1):41-7. DOI: https://doi.org/10.1006/bbrc.2002.6406 PMID: 11829459

• krzewski-2006-nk-cell-multiprotein-abstract: Krzewski K, Chen X, Orange JS, Strominger JL. Formation of a WIP-, WASp-, actin-, and myosin IIA-containing multiprotein complex in activated NK cells and its alteration by KIR inhibitory signaling. J Cell Biol. 2006;173(1):121-32. DOI: https://doi.org/10.1083/jcb.200509076 PMID: 16606694

• krzewski-2008-nk-cell-cytotoxicity-abstract: Krzewski K, Chen X, Bhardwaj N, et al. WIP is essential for lytic granule polarization and NK cell cytotoxicity. J Immunol. 2008;180(12):8312-9. DOI: https://doi.org/10.4049/jimmunol.180.12.8312 PMID: 18523299

• tsuboi-2006-monocyte-chemotaxis-abstract: Tsuboi S. A complex of Wiskott-Aldrich syndrome protein with mammalian verprolins plays an important role in monocyte chemotaxis. J Immunol. 2006;176(11):6576-85. DOI: https://doi.org/10.4049/jimmunol.176.11.6576 PMID: 16709815

• tsuboi-2007-phagocytic-cup-abstract: Tsuboi S, Meerloo J. Wiskott-Aldrich syndrome protein is a key regulator of the phagocytic cup formation in macrophages. J Biol Chem. 2007;282(47):34194-203. DOI: https://doi.org/10.1074/jbc.M705999200 PMID: 17890224

• tsuboi-2009-fbp17-abstract: Tsuboi S, Takada H, Hara T, et al. FBP17 Mediates a Common Molecular Step in the Formation of Podosomes and Phagocytic Cups in Macrophages. J Biol Chem. 2009;284(13):8548-56. DOI: https://doi.org/10.1074/jbc.M805638200 PMID: 19155218

• scott-2002-hck-wip-abstract: Scott MP, Zappacosta F, Kim EY, Annan RS, Miller WT. Identification of novel SH3 domain ligands for the Src family kinase Hck. J Biol Chem. 2002;277(31):28238-46. DOI: https://doi.org/10.1074/jbc.M202783200 PMID: 12029088

Citations

1. alonso-eiras-2024-wip-cancer-abstract.md
2. anton-1998-wip-nck-abstract.md
3. anton-2007-wip-review-abstract.md
4. chou-2006-wip-podosomes-abstract.md
5. dong-2007-wip-wasp-nfat-abstract.md
6. fried-2014-fret-wip-wasp-abstract.md
7. gallego-2005-wip-wasp-chemotaxis-abstract.md
8. garcia-2016-wip-invadopodia-abstract.md
9. janssen-2016-dock8-wip-wasp-abstract.md
10. kettner-2004-wip-mast-cells-abstract.md
11. konno-2007-wasp-wip-expression-abstract.md
12. krzewski-2006-nk-cell-multiprotein-abstract.md
13. krzewski-2008-nk-cell-cytotoxicity-abstract.md
14. lebras-2009-wip-il2-abstract.md
15. munn-2009-verprolin-review-abstract.md
16. noy-2012-wip-review-abstract.md
17. paunola-2002-wh2-review-abstract.md
18. ramesh-1997-wip-discovery-abstract.md
19. ramesh-2009-wasp-wip-advances-abstract.md
20. schwinger-2018-wip-deficiency-abstract.md
21. scott-2002-hck-wip-abstract.md
22. sokolik-2020-wip-structure-abstract.md
23. stewart-1999-wasp-wip-mutations-abstract.md
24. tsuboi-2006-monocyte-chemotaxis-abstract.md
25. tsuboi-2007-phagocytic-cup-abstract.md
26. tsuboi-2009-fbp17-abstract.md
27. vaduva-1999-wip-yeast-abstract.md
28. volkman-2002-evh1-wip-structure-abstract.md
29. zettl-2002-wh1-evh1-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research plan and verification
We verified the target is human WIPF1 (UniProt O43516), encoding WAS/WASL‑interacting protein family member 1 (WIP; aliases WASPIP, WIP). Literature consistently describes WIP as a ~503 aa, proline‑rich, verprolin‑family actin regulator that binds the N‑terminus (WH1/EVH1 domain) of WASP/N‑WASP, contains poly‑proline SH3‑binding segments, and harbors actin‑interacting motifs typical of verprolins; the organism context is Homo sapiens (human) (doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 1-3, alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 4-5).

Comprehensive research report on WIPF1 (Human)
1) Key concepts and definitions (current understanding)
- Identity and family: WIPF1 encodes WASP‑interacting protein (WIP), a core member of the verprolin/WIP family that orchestrates actin dynamics in conjunction with WASP/N‑WASP and Arp2/3. WIP is ubiquitously expressed but highest in leukocytes and is essential for immune cell cytoskeletal functions (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 1-3, alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 4-5).
- Domain architecture and interaction map: WIP is proline‑rich and modular. The C‑terminal WASP‑binding region (approximately aa 451–485) binds the N‑terminal WH1 domain of WASP/N‑WASP; Ser488 can be phosphorylated (e.g., by PKC‑θ) to regulate the WIP–WASP interaction. The central proline‑rich region recruits multiple SH3‑domain partners (e.g., Nck, CrkL) and cortactin, supporting a scaffolding function. The N‑terminal region contains actin‑interacting features (verprolin/WH2‑like properties) enabling G‑actin engagement and actin remodeling (doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 1-3, alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 4-5).
- Core molecular function: WIP binds and stabilizes WASP (and associates with N‑WASP), scaffolding Arp2/3 activation to produce branched actin networks. Loss of WIP destabilizes WASP (loss of WASP protein in WIP‑deficient human lymphocytes), leading to profound defects in polarity, migration, and immune synapse formation (Blood; doi:10.1182/blood-2017-04-777383, Oct 2017; https://doi.org/10.1182/blood-2017-04-777383) (pfajfer2017wipdeficiencyseverely pages 1-4) (alonso‐eiras2025multifacetedroleof pages 4-5).

2) Recent developments and latest research (emphasis 2023–2024, with synthesis up to 2025)
- Cancer biology: Recent syntheses highlight WIP as a context‑dependent regulator in cancer. Overexpression frequently associates with solid tumor invasion via invadopodia and ECM degradation, with WIP acting both through (N)WASP/Arp2/3 and actin‑independent stabilization of YAP/TAZ; however, WIP/WASP can have tumor‑suppressive roles in certain hematologic malignancies (e.g., selected T‑cell lymphomas). These conclusions integrate primary studies through 2023/2024 (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 10-11, alonso‐eiras2025multifacetedroleof pages 8-9, alonso‐eiras2025multifacetedroleof pages 10-10).
- Immunoactinopathies and WIP deficiency: Clinical literature consolidated in recent reviews underscores autosomal‑recessive WIPF1 loss‑of‑function as a rare “WAS‑like” immunodeficiency (sometimes referenced as WAS2), typically with severe early‑onset infections and immune dysregulation. A case series and reviews up to 2023/2024 document early life lethality in some patients (as early as 11 days–4 weeks), and a reported case with juvenile myelomonocytic leukemia (JMML) expands the phenotype spectrum (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 4-5).
- Mechanistic crosstalk with Rho GTPases and DOCK8: Contemporary mechanistic reviews emphasize a DOCK8–WIP–WASP complex linking T‑cell receptor (TCR) signals to actin cytoskeleton control, and broader crosstalk with Rho family GTPases to regulate migration and invasion in a cell‑type‑specific manner (Small GTPases; doi:10.1080/21541248.2017.1390522, Jan 2020; https://doi.org/10.1080/21541248.2017.1390522) (anton2020crosstalkbetweenwip pages 6-7). Although the review is earlier, it synthesizes mechanistic work still foundational to 2023–2024 studies.

3) Current applications and real‑world implementations
- Diagnostics: For suspected inborn errors of immunity with severe early‑onset infections/atopy and cytoskeletal phenotypes, targeted sequencing or exome/genome analysis of WIPF1 is clinically indicated. The pathognomonic cellular findings include loss of WIP and secondary loss of WASP protein with severe migration and immune synapse defects in patient lymphocytes (Blood; doi:10.1182/blood-2017-04-777383, Oct 2017; https://doi.org/10.1182/blood-2017-04-777383) (pfajfer2017wipdeficiencyseverely pages 1-4) (alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 4-5).
- Therapeutics: Hematopoietic stem cell transplantation (HSCT) is discussed as a curative option for severe WIPF1 deficiency in clinical reviews, analogous to other immunoactinopathies; preclinical/mechanistic oncology literature positions WIP pathway components (e.g., (N)WASP/Arp2/3, YAP/TAZ axes) as putative targets or biomarkers for invasion/aggressiveness, but there are no active clinical trials directly targeting WIP as of the latest synthesis (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 4-5).

4) Expert opinions and analysis from authoritative sources
- Authoritative synthesis: The 2025 Cytoskeleton review by Alonso‑Eiras and Antón, long‑standing experts in WIP biology, provides an integrated and critical analysis of WIP’s dual roles across immunity and oncology, highlighting context‑dependent tumor promotion versus suppression and urging systematic validation of WIP as a potential aggressiveness biomarker across solid tumors (doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 1-3, alonso‐eiras2025multifacetedroleof pages 8-9).
- Mechanistic consensus: The Small GTPases review emphasizes WIP’s centrality at the intersection of WASP/N‑WASP, Rho GTPases, and DOCK8 in T cells and invasive structures, a view consistent with accumulated functional data and widely accepted in the field (doi:10.1080/21541248.2017.1390522, Jan 2020; https://doi.org/10.1080/21541248.2017.1390522) (anton2020crosstalkbetweenwip pages 6-7).

5) Relevant statistics and data from recent studies
- Human WIP deficiency case quantitation: A documented human WIPF1 LoF (homozygous stop‑gain c.C373T; p.R125X) abolished WIP protein and induced loss of WASP expression in patient lymphocytes, with severe T‑cell defects (e.g., profound CD4+ lymphopenia; reduced naïve T cells; impaired chemotaxis to CCL19/CXCL12; aberrant actin polarization). This study provides concrete cellular phenotypes and directly evidenced WIP’s stabilizing effect on WASP (Blood; doi:10.1182/blood-2017-04-777383, Oct 2017; https://doi.org/10.1182/blood-2017-04-777383) (pfajfer2017wipdeficiencyseverely pages 1-4).
- Clinical timeline observations: Reviews collating reported cases indicate early‑life severe infections, with some fatalities in the first weeks of life (11 days–4 weeks), underscoring severity and need for rapid diagnosis (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 3-4).
- Mechanistic nodes and modifications: WIP Ser488 phosphorylation can disrupt WIP–WASP binding, affecting WASP stability/localization, illustrating a regulatory post‑translational control point relevant to signaling contexts (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 1-3).

Functional role and pathways
- Primary functional role: WIP is a scaffolding adapter for actin remodeling. It binds WASP/N‑WASP via its C‑terminus to stabilize these nucleation‑promoting factors and cooperates with them to activate Arp2/3‑mediated branched actin assembly. WIP also binds actin/monomeric actin via verprolin/WH2‑like features and coordinates SH3‑domain partners (e.g., Nck, CrkL) and cortactin at actin‑rich structures. These actions are essential for formation/function of immune synapses, podosomes, invadopodia, lamellipodia, and filopodia (doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 1-3, alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 10-10, alonso‐eiras2025multifacetedroleof pages 4-5).
- Pathway context: In lymphocytes, WIP sits in a DOCK8–WIP–WASP complex that relays TCR signaling to actin cytoskeleton rearrangements necessary for synapse assembly and motility; broader crosstalk with Rho GTPases modulates migration/invasion programs in other lineages (Small GTPases; doi:10.1080/21541248.2017.1390522, Jan 2020; https://doi.org/10.1080/21541248.2017.1390522) (anton2020crosstalkbetweenwip pages 6-7). WIP‑dependent stabilization of WASP is critical; in human WIP deficiency, WASP protein is lost, producing severe polarity and chemotaxis defects (Blood; doi:10.1182/blood-2017-04-777383, Oct 2017; https://doi.org/10.1182/blood-2017-04-777383) (pfajfer2017wipdeficiencyseverely pages 1-4).

Cellular and subcellular localization
- WIP localizes to cortical actin, immune synapses, podosomes/invadopodia, and other actin‑rich protrusions (filopodia/lamellipodia), often in complex with WASP/N‑WASP and cortactin; these localizations underlie its roles in migration, adhesion, and matrix remodeling (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935) (alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 10-10, alonso‐eiras2025multifacetedroleof pages 4-5). In patient lymphocytes, WIP loss disrupts front–rear polarity and immune synapse assembly, demonstrating its requirement at these sites (Blood; doi:10.1182/blood-2017-04-777383, Oct 2017; https://doi.org/10.1182/blood-2017-04-777383) (pfajfer2017wipdeficiencyseverely pages 1-4).

Human genetics and disease relevance
- Biallelic WIPF1 loss‑of‑function causes a WAS‑like primary immunodeficiency (autosomal recessive), with features including severe early‑onset infections (often viral), lymphopenia (especially naïve T cells), immune synapse defects, variable thrombocytopenia, and occasionally malignancy (e.g., JMML). Cellularly, WIP loss ablates WASP protein and cripples actin‑dependent immune functions (Cytoskeleton review; doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935; Blood case report; doi:10.1182/blood-2017-04-777383, Oct 2017) (alonso‐eiras2025multifacetedroleof pages 3-4, pfajfer2017wipdeficiencyseverely pages 1-4, alonso‐eiras2025multifacetedroleof pages 4-5).

Notes on 2023–2024 literature priorities
- While the most directly citable mechanistic and clinical anchors arise from earlier foundational work and a 2025 expert synthesis, the conclusions reflect and integrate studies published through 2023–2024 on WIP’s roles in cancer invasion (invadopodia), YAP/TAZ stabilization, and expanded immunodeficiency phenotypes. Where specific 2023–2024 primary references are needed for precision beyond this synthesis, further targeted retrieval is warranted; however, the curated review and human LoF case provide authoritative grounding for current understanding and applications (alonso‐eiras2025multifacetedroleof pages 10-11, alonso‐eiras2025multifacetedroleof pages 8-9, alonso‐eiras2025multifacetedroleof pages 10-10, alonso‐eiras2025multifacetedroleof pages 4-5).

Summary
Human WIPF1 encodes WIP, a verprolin‑family, proline‑rich adapter that binds and stabilizes WASP/N‑WASP and scaffolds SH3‑domain partners and cortactin to promote Arp2/3‑dependent actin remodeling at immune synapses, endocytic/podosome/invadopodial sites, and cortical protrusions. Loss of WIP causes a severe WAS‑like immunodeficiency by eliminating WASP protein and disrupting lymphocyte polarity, chemotaxis, and synapse formation. In cancer, WIP commonly promotes invasion via invadopodia and can stabilize pro‑oncogenic YAP/TAZ, though tumor‑suppressive roles exist in select hematologic contexts. Clinically, WIPF1 sequencing supports diagnosis of rare immunoactinopathies; HSCT is a considered therapy in severe deficiency, and WIP pathway components are candidate biomarkers/targets for tumor aggressiveness assessment (doi:10.1002/cm.21935, Sep 2025; https://doi.org/10.1002/cm.21935; doi:10.1182/blood-2017-04-777383, Oct 2017; https://doi.org/10.1182/blood-2017-04-777383; doi:10.1080/21541248.2017.1390522, Jan 2020; https://doi.org/10.1080/21541248.2017.1390522) (alonso‐eiras2025multifacetedroleof pages 1-3, alonso‐eiras2025multifacetedroleof pages 3-4, alonso‐eiras2025multifacetedroleof pages 10-11, alonso‐eiras2025multifacetedroleof pages 8-9, alonso‐eiras2025multifacetedroleof pages 10-10, pfajfer2017wipdeficiencyseverely pages 1-4, alonso‐eiras2025multifacetedroleof pages 4-5, anton2020crosstalkbetweenwip pages 6-7).

References

1. (alonso‐eiras2025multifacetedroleof pages 1-3): Jorge Alonso‐Eiras and Ines M. Anton. Multifaceted role of the actin‐binding protein wip: promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken, N.j.), 82:186-196, Sep 2025. URL: https://doi.org/10.1002/cm.21935, doi:10.1002/cm.21935. This article has 2 citations.

2. (alonso‐eiras2025multifacetedroleof pages 3-4): Jorge Alonso‐Eiras and Ines M. Anton. Multifaceted role of the actin‐binding protein wip: promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken, N.j.), 82:186-196, Sep 2025. URL: https://doi.org/10.1002/cm.21935, doi:10.1002/cm.21935. This article has 2 citations.

3. (alonso‐eiras2025multifacetedroleof pages 4-5): Jorge Alonso‐Eiras and Ines M. Anton. Multifaceted role of the actin‐binding protein wip: promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken, N.j.), 82:186-196, Sep 2025. URL: https://doi.org/10.1002/cm.21935, doi:10.1002/cm.21935. This article has 2 citations.

4. (pfajfer2017wipdeficiencyseverely pages 1-4): Laurène Pfajfer, Markus G. Seidel, Raïssa Houmadi, Javier Rey-Barroso, Tatjana Hirschmugl, Elisabeth Salzer, Inés María Antón, Christian Urban, Wolfgang Schwinger, Kaan Boztug, and Loïc Dupré. Wip deficiency severely affects human lymphocyte architecture during migration and synapse assembly. Blood, 130 17:1949-1953, Oct 2017. URL: https://doi.org/10.1182/blood-2017-04-777383, doi:10.1182/blood-2017-04-777383. This article has 41 citations and is from a highest quality peer-reviewed journal.

5. (alonso‐eiras2025multifacetedroleof pages 10-11): Jorge Alonso‐Eiras and Ines M. Anton. Multifaceted role of the actin‐binding protein wip: promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken, N.j.), 82:186-196, Sep 2025. URL: https://doi.org/10.1002/cm.21935, doi:10.1002/cm.21935. This article has 2 citations.

6. (alonso‐eiras2025multifacetedroleof pages 8-9): Jorge Alonso‐Eiras and Ines M. Anton. Multifaceted role of the actin‐binding protein wip: promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken, N.j.), 82:186-196, Sep 2025. URL: https://doi.org/10.1002/cm.21935, doi:10.1002/cm.21935. This article has 2 citations.

7. (alonso‐eiras2025multifacetedroleof pages 10-10): Jorge Alonso‐Eiras and Ines M. Anton. Multifaceted role of the actin‐binding protein wip: promotor and inhibitor of tumor progression and dissemination. Cytoskeleton (Hoboken, N.j.), 82:186-196, Sep 2025. URL: https://doi.org/10.1002/cm.21935, doi:10.1002/cm.21935. This article has 2 citations.

8. (anton2020crosstalkbetweenwip pages 6-7): Inés M. Antón, Carla Gómez-Oro, Sergio Rivas, and Francisco Wandosell. Crosstalk between wip and rho family gtpases. Small GTPases, 11:160-166, Jan 2020. URL: https://doi.org/10.1080/21541248.2017.1390522, doi:10.1080/21541248.2017.1390522. This article has 15 citations and is from a peer-reviewed journal.

Citations

1. pfajfer2017wipdeficiencyseverely pages 1-4
2. anton2020crosstalkbetweenwip pages 6-7
3. https://doi.org/10.1002/cm.21935
4. https://doi.org/10.1182/blood-2017-04-777383
5. https://doi.org/10.1080/21541248.2017.1390522
6. https://doi.org/10.1002/cm.21935;
7. https://doi.org/10.1182/blood-2017-04-777383;
8. https://doi.org/10.1002/cm.21935,
9. https://doi.org/10.1182/blood-2017-04-777383,
10. https://doi.org/10.1080/21541248.2017.1390522,

WIPF1 (WASP-Interacting Protein 1) – Structure, Function, and Recent Insights

Overview and Key Concepts

WIPF1 (WAS/WASL-Interacting Protein Family Member 1), often called Wiskott–Aldrich Syndrome Protein-Interacting Protein (WIP), encodes a 503–amino-acid adaptor protein crucial for actin cytoskeleton organization (en.wikipedia.org). First identified in 1997, WIP was shown to induce actin polymerization and cytoskeletal reorganization in lymphoid cells (en.wikipedia.org). It belongs to the verprolin family of actin-binding proteins, reflecting its evolutionary conservation (e.g. yeast Vrp1/verprolin is a homolog) (www.reactome.org). WIPF1 is expressed ubiquitously in humans (with high levels in immune tissues like blood cells, spleen, thymus, and also placenta) (www.reactome.org). Notably, WIP is named for its interaction with the Wiskott–Aldrich Syndrome protein (WASp); this interaction underpins WIP’s biological role and links it to the immunodeficiency disorder Wiskott–Aldrich syndrome (en.wikipedia.org). In cells, WIP functions as a scaffold/adaptor that links signaling molecules to the actin polymerization machinery, rather than as an enzyme – it has no catalytic activity, but its binding partners and domains enable it to regulate actin dynamics in space and time.

Protein domains and structure: WIPF1’s protein product contains several defined motifs that mediate its interactions (see Figure 1 for domain map). It has an N-terminal profilin-binding domain, which can bind profilin–actin complexes (en.wikipedia.org). Profilin is an actin-monomer binding protein, so this interaction helps tether actin monomers. WIP also contains two WH2 (Wiscott–Aldrich homology 2) domains (verprolin homology motifs) that directly bind globular actin (G-actin) (en.wikipedia.org). These WH2 domains allow WIP to sequester or position actin monomers near sites of filament assembly. A central proline-rich region enables WIP to bind SH3-domain proteins – for example, it can bind to the adaptor Nck and other SH3-containing partners (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Finally, the C-terminus of WIP contains a WASP-binding domain that binds tightly to the N-terminal EVH1 (WH1) domain of WASP and N-WASP (en.wikipedia.org). This WIP–WASP interaction is constitutive (WIP and WASP form a stable complex in resting cells) and is functionally critical: most disease-causing mutations in WASP occur in its EVH1 domain and disrupt WIP binding (en.wikipedia.org). Structural studies have shown that a 25-residue segment of WIP wraps around the EVH1 domain of N-WASP/WASP, forming an extensive interface; this explains why many Wiskott–Aldrich Syndrome mutations (EVH1 missense mutations) destabilize the WIP–WASP complex (pubmed.ncbi.nlm.nih.gov). In the absence of WIP, WASP is unstable and prone to degradation, as observed in both WIP-deficient patients and knockout models (rupress.org). Thus, WIP’s domains collectively allow it to bind actin monomers, actin-polymerization factors (profilin), and key regulators like WASP/N-WASP, positioning WIP as a central organizer of actin assembly.

Role in Actin Polymerization and Cytoskeletal Regulation

WIP is best understood for its role in regulating actin polymerization through the Arp2/3 complex pathway. WASP and N-WASP (the proteins that WIP binds) are actin nucleation-promoting factors: upon activation, WASP/N-WASP use their C-terminal VCA domain to activate the Arp2/3 complex, which in turn nucleates new actin filaments (creating branched actin networks) (pmc.ncbi.nlm.nih.gov). WIP itself does not nucleate actin, but it modulates this process by controlling the availability and activity of WASP/N-WASP and actin monomers at the membrane. In resting cells, WIP bound to WASP can help keep WASP in an inactive but stable state – preventing its degradation yet also potentially masking interactions until the right signals arrive (en.wikipedia.org) (rupress.org). When an upstream signal (for example, from a cell-surface receptor) triggers Cdc42 or other pathways that activate WASP/N-WASP, WIP participates in recruiting and localizing WASP to the proper subcellular site (www.reactome.org). WIP works together with adaptor proteins like Nck and Grb2 to target WASP/N-WASP to the plasma membrane or to forming actin structures (www.reactome.org). Notably, WIP’s interaction with Nck (via its proline-rich motif binding Nck’s SH3 domain) couples receptor signaling to actin polymerization: Nck is often recruited to phosphorylated receptor complexes, and it can carry WIP–WASP complexes with it (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This positioning allows WASP to encounter its activators (like Cdc42 or PIP₂) at the membrane and then trigger Arp2/3-mediated actin assembly.

Influence on actin structures: By tethering WASP/N-WASP and actin, WIP orchestrates the formation of specialized actin-rich structures. For example, filopodia (spike-like membrane protrusions) and lamellipodia (broad membrane ruffles) are both actin-driven structures that require coordinated nucleation and elongation of actin filaments. WIP promotes filopodium formation in cooperation with N-WASP under the control of active Cdc42 (pmc.ncbi.nlm.nih.gov). In addition, WIP is required for efficient lamellipodia formation in response to stimuli like PDGF (Platelet-Derived Growth Factor) (pmc.ncbi.nlm.nih.gov). Mechanistically, WIP–WASP complexes at the leading edge help initiate new actin branches via Arp2/3, while also possibly disassembling older actin stress fibers, thus shifting the cytoskeletal architecture from contractile bundles to protrusive networks (www.reactome.org). In vitro and cellular overexpression studies support WIP’s pro-polymerizing role: overexpressing WIP in mammalian cells enhances actin polymerization and drives redistribution of actin filaments (en.wikipedia.org). Conversely, when WIP is removed or mutated, cells show defective actin assembly – for instance, WIP-deficient fibroblasts or immune cells have trouble forming normal lamellipodia and filopodia, highlighting WIP’s indispensable role in actin network formation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Importantly, WIP can also bind actin directly via its WH2 domains, and this direct WIP–actin interaction is biologically essential. An elegant study in knockout mice demonstrated that T cells expressing a WIP mutant unable to bind actin (but still able to bind WASP) exhibit severe cytoskeletal defects (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These WIP mutant T cells maintained normal WASP levels (since WIP still bound WASP to stabilize it) but had reduced F-actin content, disorganized filament architecture, and impaired cell polarization and migration (pmc.ncbi.nlm.nih.gov). They failed to crawl normally and could not home to lymphoid organs effectively (pmc.ncbi.nlm.nih.gov). This indicates that WIP’s direct binding to actin monomers or filaments is needed to maintain the integrity of the actin cytoskeleton in cells. By binding actin, WIP may cluster actin monomers near WASP, facilitating efficient nucleation and elongation. Additionally, WIP-bound actin might help anchor the WIP–WASP complex to existing filaments, aiding branching. Thus, both arms of WIP’s function – bridging to WASP and directly binding actin – converge to promote proper actin polymerization.

Localization and Interactions of WIPF1 Protein

Subcellular localization: WIP is predominantly a cytosolic protein that concentrates at areas of active actin remodeling. It lacks transmembrane domains and does not enter the secretory pathway, so it functions inside the cell. Studies have shown that WIP co-localizes with actin filaments – for example, it is seen along actin stress fibers in fibroblasts and at the cortical actin network in various cells (www.reactome.org). When WIP is expressed with N-WASP, it tends to accumulate in the same regions as N-WASP (e.g. at the cell periphery and in perinuclear puncta), rather than along bundled actin, reflecting the formation of WIP–WASP complexes that relocate together (www.reactome.org). WIP is also found at specialized actin structures: it localizes to the invadopodia of cancer cells and podosomes of normal cells (these are actin-rich adhesive protrusions – described further below) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Furthermore, WIP can associate with vesicular membranes that are undergoing actin-driven movement. One striking example is during vaccinia virus infection: vaccinia hijacks the host actin machinery to propel itself, forming “actin comet tails” on the virus. WIP is actively recruited to vaccinia virions on endosomal membranes and serves as an adapter to bring N-WASP to the virus surface, enabling actin polymerization that drives the virus through the cell (www.reactome.org). In cells lacking WIP or WASP, vaccinia virus motility is greatly impaired, underscoring WIP’s role in linking actin to membrane-bound cargos (www.reactome.org). In summary, WIP is usually found in the cytoplasm at or near the plasma membrane, wherever dynamic actin assembly is occurring (ruffles, microvilli, immune synapses, etc.), rather than in the nucleus or extracellular space.

Protein–protein interactions: As an adaptor, WIPF1 protein interacts with numerous partners to execute its function. Its primary binding partner is WASP (in hematopoietic cells) or N-WASP (ubiquitously) (en.wikipedia.org). WIP forms a tight complex with WASP via the C-terminus, and similarly can bind N-WASP (WASL) in other cell types (en.wikipedia.org). Beyond WASP, WIP binds actin (G-actin and possibly F-actin) and profilin–actin complexes as noted. WIP’s proline-rich segment allows it to engage several SH3-domain-containing signaling adaptors. Key among these is Nck1, an adapter that links receptor tyrosine kinases or T-cell receptor signaling to actin regulation; WIP and Nck1 interact directly, which helps recruit the WIP–WASP complex to activated receptors (en.wikipedia.org) (pmc.ncbi.nlm.nih.gov). WIP also binds the Cortactin protein (en.wikipedia.org) – cortactin is an actin-binding scaffolding protein enriched in invadopodia and at the immunological synapse. Through binding cortactin, WIP may help coordinate actin polymerization with matrix degradation, since cortactin scaffolds the machinery that brings metalloproteinases (MMPs) to invasive protrusions (pmc.ncbi.nlm.nih.gov). Another known WIP partner is NCK/ITSN1 (Intersectin-1), an endocytic adaptor; WIP might participate in endocytosis or receptor trafficking via this interaction (en.wikipedia.org). WIP binds MYO1e (myosin 1e) (en.wikipedia.org), an unconventional myosin that links actin to membranes, suggesting WIP could help attach actin filaments to membrane structures during movement. Additionally, WIP interacts with FNBP1L (Toca-1) (www.reactome.org), an SH3-domain protein that, together with N-WASP, is involved in endocytic vesicle formation and actin nucleation. Through FNBP1L and the related protein ITSN, WIP–WASP may be recruited to sites of clathrin-mediated endocytosis, promoting actin assembly for vesicle internalization (www.reactome.org). WIP’s N-terminal region (residues 45–48) contains a KLKK motif that binds actin (pmc.ncbi.nlm.nih.gov), and also a profilin-binding site, highlighting how WIP can simultaneously connect to monomeric actin (via KLKK/WH2) and profilin–actin complexes. This multiplicity of interactions enables WIP to serve as a hub where signaling molecules (like Nck, protein kinases), actin regulators (profilin, cortactin), and actin itself all converge.

Biological Functions in Immune Cells and Beyond

One of the most critical roles of WIPF1 is in the immune system, where its interplay with WASP is vital for immune cell function. WASP is expressed only in blood lineage cells (leukocytes), and WIP is highly expressed in these cells as well (en.wikipedia.org). In T lymphocytes, WIP is essential for forming the immune synapse – the specialized junction between a T cell and an antigen-presenting cell. During T cell activation, the T cell receptor (TCR) triggers a burst of actin polymerization at the contact site, creating a platform for signaling. WIP is required to concentrate F-actin at the edge of the immunological synapse, enabling the T cell to spread and form a tight contact (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Experiments show that WIP-deficient T cells cannot properly polarize their actin cytoskeleton upon TCR engagement, leading to an impaired synapse and reduced signaling (e.g. poor IL-2 secretion) (pmc.ncbi.nlm.nih.gov). In WIP knockout mice, T cells proliferate poorly in response to stimulation and fail to sustain contact with antigen-presenting cells (pmc.ncbi.nlm.nih.gov). This is because without WIP, WASP is absent (degraded) and Arp2/3-driven actin nucleation is greatly compromised, so the T cell can’t reorganize its cytoskeleton effectively. Interestingly, while WIP positively regulates T-cell activation (by promoting actin remodeling at the synapse), it has an opposite effect in B cells: WIP acts as a negative regulator of B-cell receptor signaling. WIP-deficient B cells show enhanced proliferation and upregulated activation markers upon B-cell receptor stimulation (pmc.ncbi.nlm.nih.gov). In WIP knockout mice, B cells produce abnormally high levels of IgM and IgE antibodies and tend to hyper-respond, which is associated with autoimmune symptoms (pmc.ncbi.nlm.nih.gov). This dichotomy suggests WIP helps maintain a balance in the immune system: it’s required for full T-cell activation, but also serves to restrain B-cell activation to prevent overreaction. The net result in WIP-deficient mice is a mix of immunodeficiency (due to T-cell dysfunction) and autoimmune features (due to unrestrained B cells) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Other immune cells are also affected: Natural Killer (NK) cells from WIP-deficient patients fail to properly polarize lytic granules towards their targets, leading to defective cytotoxicity (pmc.ncbi.nlm.nih.gov). Similarly, dendritic cells and macrophages rely on WIP for forming podosomes – actin-rich adhesive structures needed for migration and tissue invasion (pmc.ncbi.nlm.nih.gov). Without WIP, these myeloid cells can’t form normal podosomes, impairing processes like wound healing and immune cell trafficking (pmc.ncbi.nlm.nih.gov).

Beyond the immune system, WIP participates in various cellular processes that require actin remodeling. In the nervous system, studies in mice suggest WIP has a role in regulating neurite outgrowth. Neurons from WIP-knockout mice showed accelerated neurite initiation and excessive branching, implying that WIP normally acts as a brake on early neurite formation (pmc.ncbi.nlm.nih.gov). The mechanism appears to involve signaling crosstalk: WIP deficiency led to overactivation of mTORC1–S6K signaling, which promotes neurite growth (pmc.ncbi.nlm.nih.gov). Thus, WIP might link actin dynamics to signaling pathways that control neural development, ensuring proper timing of neurite extension. In the context of pathogen infection, as mentioned, WIP is co-opted by vaccinia virus to facilitate its spread (www.reactome.org). There is evidence that other pathogens may also exploit WIP or its partners for actin-based motility: for instance, certain intracellular bacteria (like Listeria or Shigella) and viruses create actin “comet tails,” and proteins like N-WASP/WIP are often involved (pmc.ncbi.nlm.nih.gov). WIP’s ability to localize actin polymerization activity makes it a target for such viral/bacterial strategies to move within cells. Additionally, WIP is involved in cell migration generally. Fibroblasts lacking WIP have motility defects; conversely, WIP overexpression can increase cell migration speed (though often with less directional persistence) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). WIP also contributes to the formation of invadopodia in cancer cells – these are invasive protrusions that degrade extracellular matrix. We will discuss this further in the disease context, but biologically, invadopodia are similar to the podosomes of immune cells, and WIP–N-WASP–Arp2/3 are key components of both (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In summary, WIPF1’s normal functions span any cellular context where actin remodeling is critical: immune synapse assembly, cell migration, morphogenesis (neurite formation), and membrane trafficking. Its role is to ensure actin polymerization occurs at the right place and is integrated with the cell’s signaling cues.

Clinical Significance and Disease Associations

Immunodeficiency (WIPF1 mutations): Given WIP’s central partnership with WASP, it is unsurprising that defects in WIPF1 can lead to immunological disease resembling Wiskott–Aldrich Syndrome (WAS). WAS is an X-linked disorder caused by WASP mutations; patients have eczema, recurrent infections, thrombocytopenia (low platelets), and T-cell/B-cell dysfunction. In 2012, the first human case of WIPF1 deficiency was reported: a young girl with a WAS-like syndrome but no mutation in her WAS gene (en.wikipedia.org) (en.wikipedia.org). Genetic analysis found a homozygous loss-of-function mutation in WIPF1 (en.wikipedia.org). This WIP-deficient patient presented with severe recurrent infections, eczema, and thrombocytopenia – closely mirroring classic WAS (en.wikipedia.org). Cellular analysis confirmed that in the absence of WIP, WASP protein was completely depleted, explaining the immunodeficient phenotype (rupress.org). The patient’s T cells showed instability of the actin cytoskeleton and failed immune synapse formation, and NK cells had defective granule polarization (pmc.ncbi.nlm.nih.gov), consistent with what WIP-knockout mice predicted. A second case series in 2017 (Pfajfer et al.) identified additional patients with WIPF1 mutations, who likewise showed combined immunodeficiency and some developmental delays (pmc.ncbi.nlm.nih.gov). These cases establish WIPF1 deficiency as a rare primary immunodeficiency disorder. From a clinical standpoint, if a patient exhibits WAS-like symptoms but tests negative for WAS gene mutations, sequencing of WIPF1 is warranted. There is no official name for this condition yet (sometimes it’s considered within the WAS spectrum); treatment has involved bone marrow transplantation, similar to WAS (rupress.org). Notably, most WIP-deficient patients have undetectable WASP protein, confirming that WIP is essential for WASP stability in vivo (rupress.org). Even partial loss of WIP function (e.g. a mutation that weakens WIP–actin binding without fully ablating the protein) can impair immune cell function significantly (pmc.ncbi.nlm.nih.gov). Thus, WIPF1 is as critical as WASP for healthy immune function, and it underscores how adaptor proteins can be linchpins in signaling pathways.

Cancer and metastasis: Emerging research shows that WIPF1 also plays important roles in cancer cell behavior, particularly in cell migration, invasion, and metastasis. Many cancers exhibit dysregulated actin cytoskeleton dynamics to facilitate tumor spread, and WIP appears to be a key permissive factor for this. In most solid tumors, studies have found that WIP is upregulated and contributes to aggressive tumor phenotypes (pmc.ncbi.nlm.nih.gov). High WIP expression has been correlated with advanced disease and poorer patient outcomes in several cancer types, including lung, gastric, pancreatic, and others (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). For example, a 2023 analysis in gastric cancer patients showed that tumors with elevated WIPF1 levels were associated with worse prognosis (shorter overall survival) (pmc.ncbi.nlm.nih.gov). Functional experiments in gastric cancer cell lines demonstrated that WIP drives tumor progression by enhancing PI3K–Akt signaling in a myocardin-dependent manner (pmc.ncbi.nlm.nih.gov). When WIPF1 was knocked down in these cancer cells, their proliferation, migration, and invasiveness all decreased, supporting WIP as a pro-tumor factor (pmc.ncbi.nlm.nih.gov). Similarly, in non-small cell lung cancer (NSCLC), high WIP was linked to greater malignancy: one mechanism involves PD-L1 (an immune checkpoint protein) triggering β-catenin signaling which upregulates WIPF1, thereby promoting tumor cell survival and colony formation (pmc.ncbi.nlm.nih.gov). In lung adenocarcinoma models (A549 cells), overexpression of WIP induced a more mesenchymal and invasive phenotype, with increased cell motility and markers of epithelial–mesenchymal transition (EMT) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Conversely, reducing WIP in these cells can reverse some of the invasive characteristics (pmc.ncbi.nlm.nih.gov).

WIP’s role in invasion is tied to its function in forming invadopodia – the actin-rich protrusions by which cancer cells degrade and penetrate the extracellular matrix. WIP, together with N-WASP, is required for invadopodium formation and maturation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In breast cancer cells, for instance, loss of WIP impairs the formation of functional invadopodia, reducing matrix degradation and cell invasion (pmc.ncbi.nlm.nih.gov). WIP recruits and interacts with cortactin and Nck in invadopodia, similar to its role in immune cell podosomes, to organize the actin core and to localize matrix metalloproteinase (MMP) delivery to the proper sites (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This is one reason WIP overexpression often confers metastatic potential: tumors can more readily break through tissue barriers. On a signaling level, WIP has been implicated in activating YAP/TAZ, the effectors of the Hippo pathway, which promote cell proliferation and survival. Research in pancreatic ductal adenocarcinoma found that microRNAs which suppress WIP led to reduced YAP/TAZ activity and less tumor invasion, while high WIP correlated with shorter patient survival (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In summary, high WIPF1 levels in tumors create a cellular environment conducive to metastasis: stronger actin-based motility, more invasive structures, and enhanced pro-survival signaling. This has made WIP of interest as a potential biomarker for cancer prognosis (pmc.ncbi.nlm.nih.gov). Indeed, WIPF1 is included in some gene signatures predicting poor outcome and therapy resistance in cancers such as head-neck squamous carcinoma and others (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). It’s important to note that WIP’s role can be context-dependent – intriguingly, some hematological cancers (leukemias/lymphomas) show the opposite trend, where WIP might act as a suppressor of tumor growth (pmc.ncbi.nlm.nih.gov). The reasons are not fully clear, but it might relate to WIP’s role in immune cells: for instance, WIP deficiency can cause hyper-activation of B cells, so loss of WIP in a B-cell lineage malignancy could conceivably promote proliferation. Nonetheless, the predominant theme in solid tumors is that WIP promotes tumor progression. From a therapeutic angle, targeting WIPF1 or its binding interfaces (e.g. disrupting WIP–WASP or WIP–actin interactions) is a novel idea. No WIP-targeted therapies exist yet, but researchers speculate that inhibiting WIP function might reduce cancer invasiveness and could be synergistic with therapies like immune checkpoint blockade (given the PD-L1–WIP connection) (pmc.ncbi.nlm.nih.gov).

Development and other contexts: A recent line of research has identified WIPF1 as important in developmental invasion processes, such as placental development. A 2023 study highlighted that WIPF1 is highly expressed in human placental extravillous trophoblasts (EVTs) during the first trimester (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). EVTs invade the uterine lining to establish blood supply for the fetus, a process conceptually similar to cell invasion in cancer (but tightly regulated). WIPF1 was found to be crucial for proper EVT invasion: knockdown of WIPF1 in trophoblast cells significantly impaired their migration and invasion, while overexpression enhanced invasion (pubmed.ncbi.nlm.nih.gov). WIP was shown to form a complex with actinin-4 (ACTN4), and this WIP–ACTN4 complex is involved in forming podosomes in trophoblasts, which are needed for establishing anchorage in the uterus (the study linked WIPF1 deficits to cases of recurrent spontaneous abortion) (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). This finding underscores WIP’s role in physiological invasion processes and suggests that beyond disease, WIP is required for normal human development (in this case, successful pregnancy). Another context being explored is WIP’s role in redox homeostasis in cancer cells: for instance, in glioblastoma, WIP was found to stabilize the transcription factor NRF2 (a master antioxidant regulator) by altering actin dynamics that affect the KEAP1–NRF2 degradation pathway (pmc.ncbi.nlm.nih.gov). This indicates WIP’s influence may extend to signaling pathways beyond actin itself (e.g., impacting gene expression indirectly via cytoskeletal changes). Overall, the involvement of WIPF1 in diverse contexts – immune function, development, cancer – all pivot on its core function of regulating the actin cytoskeleton. In each scenario, the precise role of WIPF1 is to localize and modulate actin polymerization in concert with specific partners, thereby enabling cellular processes like synapse formation, migration, or invasion.

Recent Developments and Expert Perspectives (2023–2024)

Research on WIPF1 has been active, with several 2023–2024 studies and reviews providing new insights. A notable publication in late 2024 (Alonso-Eiras & Antón, Cytoskeleton, Sep 2024) reviewed WIP’s roles and described it as a “double-edged sword” in pathology (pmc.ncbi.nlm.nih.gov). According to this review, WIP needs to be tightly regulated in the body: both an absence of WIP and an excess of WIP can lead to disease (pmc.ncbi.nlm.nih.gov). On one hand, loss-of-function mutations in WIPF1 cause severe immunodeficiency in humans (early-onset infections, autoimmunity, etc.), consistent with WIP’s essential role in the immune system (pmc.ncbi.nlm.nih.gov). On the other hand, overexpression of WIP is linked to cancer progression and even aging-related pathologies (pmc.ncbi.nlm.nih.gov). This duality is prompting researchers to dissect context-specific effects – for instance, why WIP overexpression is pro-tumorigenic in most solid cancers, yet WIP might restrain certain leukemias (pmc.ncbi.nlm.nih.gov). The 2024 review emphasizes that WIP performs some functions independent of actin polymerization, such as stabilizing the oncogenic transcription co-activators YAP/TAZ, which could contribute to tumor growth even when actin dynamics are not limiting (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). The authors highlight the need for further research to identify WIP’s binding partners in various contexts and to explore if WIP could be a drug target in oncology (pmc.ncbi.nlm.nih.gov). They also note WIP’s involvement in fundamental processes, labeling it a “major regulator of actin dynamics with essential roles for a healthy immune system” (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

From a data perspective, recent studies have provided quantitative links between WIPF1 expression and clinical outcomes. For example, Su et al. (2023) reported that gastric cancer patients with high WIPF1 expression had significantly lower 5-year survival rates compared to those with low expression (pmc.ncbi.nlm.nih.gov). In pancreatic cancer, analysis of The Cancer Genome Atlas (TCGA) data showed that low WIPF1 expression correlated with longer overall survival, whereas high WIPF1 was a marker of poor prognosis (p < 0.01) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Large-scale profiling has also identified WIPF1 as part of an “EMT gene signature” that predicts metastasis; WIPF1 was flagged as a differentially expressed hub gene in head and neck cancers that progress versus those that do not (pmc.ncbi.nlm.nih.gov). Such bioinformatic and clinical studies underscore WIPF1’s relevance as a biomarker. In immunology, a 2023 study on WIP-knockout mice (Gadjalova et al., 2024) reinforced earlier findings by showing WIP deficiency leads to systemic autoimmunity (e.g. colitis and aberrant lymphocyte populations) due to cytoskeletal dysregulation in immune cells (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This suggests that therapies modulating actin regulators like WIP could potentially alleviate certain inflammatory conditions, though this idea is still speculative.

Another fresh development is the exploration of WIPF1 in reproductive medicine, as mentioned. The identification of WIPF1’s role in trophoblast invasion (2023) opens doors to investigating whether WIPF1 mutations or dysregulation contribute to pregnancy disorders such as recurrent miscarriages or preeclampsia. This is an example of how new research extends WIP’s significance beyond the immune and cancer fields.

Expert opinions: Leaders in the field, such as Dr. Inés Antón (a co-discoverer of WIP and author of multiple WIP studies), note that WIP is “a master coordinator of actin reorganization” and that its proper function is crucial for cellular health (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Her analyses point out that WIP’s multi-domain structure allows it to integrate signals – from Rho GTPases like Cdc42, to kinases, to membrane phospholipids – and translate them into precise actin assembly events (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Another expert perspective (from the 2024 Cytoskeleton review) is that targeting the WIP/WASP interface might be an attractive strategy in cases ranging from immunodeficiency to cancer (pmc.ncbi.nlm.nih.gov). For instance, stabilizing WIP–WASP interaction might help in conditions where WASP is unstable (as a therapeutic approach for certain WAS patients), whereas inhibiting WIP–WASP or WIP–actin interactions might slow down cancer cell invasion (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). However, such interventions would require extreme caution given WIP’s ubiquity and importance in normal cells.

In conclusion, WIPF1 encodes a pivotal actin-regulatory adaptor that connects the Wiskott–Aldrich Syndrome protein (WASP) to the actin cytoskeleton and to signaling networks. Its primary function is to coordinate actin filament nucleation and remodeling at specific cellular sites, enabling processes like immune synapse formation, cell motility, and invasion. WIPF1 operates at the nexus of multiple pathways: it interacts with key signaling proteins (Nck, GRB2, cortactin), structural proteins (actin, profilin), and membrane components, thereby serving as a bridge between signals and the actin machinery. This precise role has broad implications – loss of WIPF1 cripples immune cell function and causes immunodeficiency, while excess WIPF1 endows cells with enhanced invasive capabilities and is linked to metastasis and poor clinical outcomes in cancer. Current research (2023–2024) is actively uncovering new facets of WIPF1, from its involvement in placental development to its regulation of transcription factors in cancer, highlighting that WIPF1’s influence extends beyond actin polymerization alone. Moving forward, WIPF1 remains a subject of intense study, both to fully delineate how this protein maintains cellular cytoskeletal health and to exploit its dysfunction in disease contexts for potential therapies. Each new discovery reinforces the concept that controlling the actin cytoskeleton through molecules like WIPF1 is fundamental to cell biology and human health (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

References: (Publication dates and sources)
- Kolluri R. et al. (1997). “WIP, a protein associated with Wiskott–Aldrich syndrome protein, induces actin polymerization and redistribution in lymphoid cells.” Proc Natl Acad Sci USA 94(26):14671–14676 (en.wikipedia.org).
- Lanzi G. et al. (2012). “A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP.” J. Exp. Med. 209(1):29–34 (Jan 16, 2012) (en.wikipedia.org) (rupress.org).
- Massaad M. et al. (2014). “Binding of WIP to actin is essential for T cell actin cytoskeleton integrity and tissue homing.” Mol. Cell. Biol. 34(23):4343–54 (Dec 2014) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
- Su F. et al. (2023). “WIP promotes tumor progression by regulating PI3K/Akt signaling in gastric cancer.” Cell. Oncol. 46(8):1063–1080 (Aug 2023) (pmc.ncbi.nlm.nih.gov).
- Alonso-Eiras J., Antón I.M. (2024). “Multifaceted role of the actin-binding protein WIP: promoter and inhibitor of tumor progression and dissemination.” Cytoskeleton 82(3):186–196 (Sep 27, 2024) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
(Additional citations are embedded in text above for specific claims and data.)

Citations

1. AnnotationURLCitation(end_index=475, start_index=332, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=This%20gene%20encodes%20a%20protein,depleted%20and%20WAS%20symptoms%20present')
2. AnnotationURLCitation(end_index=711, start_index=598, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=,interacting%20protein%20family%2C%20member%201')
3. AnnotationURLCitation(end_index=1011, start_index=865, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=of%20functional%20WASL,67280%20description')
4. AnnotationURLCitation(end_index=1321, start_index=1144, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=cortical%20areas%20like%20WASL%20,Belongs%20to%20the%20verprolin%20family')
5. AnnotationURLCitation(end_index=1681, start_index=1535, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=to%20increase%20actin%20polymerization,depleted%20and%20WAS%20symptoms%20present')
6. AnnotationURLCitation(end_index=2318, start_index=2204, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=affect%20WASp,WASp%20remains%20stable%20in%20the')
7. AnnotationURLCitation(end_index=2672, start_index=2558, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=affect%20WASp,WASp%20remains%20stable%20in%20the')
8. AnnotationURLCitation(end_index=3041, start_index=2933, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=breast%20cancer%20,2016')
9. AnnotationURLCitation(end_index=3239, start_index=3042, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=For%20effective%20proteolysis%20of%20the,transcriptional%20activator%20E26%20transformation%20specific%E2%80%901')
10. AnnotationURLCitation(end_index=3495, start_index=3381, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=affect%20WASp,WASp%20remains%20stable%20in%20the')
11. AnnotationURLCitation(end_index=3817, start_index=3715, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=N,WASp%20remains%20stable%20in%20the')
12. AnnotationURLCitation(end_index=4225, start_index=4076, title='Structure of the N-WASP EVH1 domain-WIP complex: insight into the molecular basis of Wiskott-Aldrich Syndrome - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/12437929/#:~:text=Missense%20mutants%20that%20cause%20the,This%20recognition%20mechanism')
13. AnnotationURLCitation(end_index=4490, start_index=4360, title='A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP | Journal of Experimental Medicine | Rockefeller University Press', type='url_citation', url='https://rupress.org/jem/article-abstract/209/1/29/40968#:~:text=%28Fig,to%20examine%20whether%20transduction%20of')
14. AnnotationURLCitation(end_index=5301, start_index=5135, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L87%20Cdc42%20activates,to%20move%20through%20interstitial%20tissues')
15. AnnotationURLCitation(end_index=5806, start_index=5660, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=to%20increase%20actin%20polymerization,depleted%20and%20WAS%20symptoms%20present')
16. AnnotationURLCitation(end_index=5937, start_index=5807, title='A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP | Journal of Experimental Medicine | Rockefeller University Press', type='url_citation', url='https://rupress.org/jem/article-abstract/209/1/29/40968#:~:text=%28Fig,to%20examine%20whether%20transduction%20of')
17. AnnotationURLCitation(end_index=6302, start_index=6157, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=,Vesicle%20surfaces%20and%20along%20actin')
18. AnnotationURLCitation(end_index=6588, start_index=6443, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=,Vesicle%20surfaces%20and%20along%20actin')
19. AnnotationURLCitation(end_index=7034, start_index=6837, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=For%20effective%20proteolysis%20of%20the,transcriptional%20activator%20E26%20transformation%20specific%E2%80%901')
20. AnnotationURLCitation(end_index=7159, start_index=7035, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=al,MMP2%2C%20and%20MMP9%20is%20produced')
21. AnnotationURLCitation(end_index=7931, start_index=7756, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=formation%20of%20actin%E2%80%90rich%20structures%20including,A%20WIP%2FWASP%20complex%20is')
22. AnnotationURLCitation(end_index=8244, start_index=8069, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=formation%20of%20actin%E2%80%90rich%20structures%20including,A%20WIP%2FWASP%20complex%20is')
23. AnnotationURLCitation(end_index=8645, start_index=8500, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=,Vesicle%20surfaces%20and%20along%20actin')
24. AnnotationURLCitation(end_index=8991, start_index=8848, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=This%20gene%20encodes%20a%20protein,depleted%20and%20WAS%20symptoms%20present')
25. AnnotationURLCitation(end_index=9378, start_index=9256, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%20is%20not%20necessary%20for,2002')
26. AnnotationURLCitation(end_index=9544, start_index=9379, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=polarization%20%28Ant%C3%B3n%20et%20al,immune%20system%20have%20been%20partially')
27. AnnotationURLCitation(end_index=10001, start_index=9858, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=The%20Wiskott,actin%20content%2C%20a%20disorganized%20actin')
28. AnnotationURLCitation(end_index=10156, start_index=10002, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=that%20lack%20the%20actin,from%20WIP%CE%94ABD%20mice%20had%20decreased')
29. AnnotationURLCitation(end_index=10503, start_index=10372, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=,defect%20in%20contact%20hypersensitivity%20and')
30. AnnotationURLCitation(end_index=10739, start_index=10585, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=that%20lack%20the%20actin,from%20WIP%CE%94ABD%20mice%20had%20decreased')
31. AnnotationURLCitation(end_index=11906, start_index=11711, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=the%20SH3%20domain%29%20%28PubMed%3A19798448%29,ALTERNATIVE%20PRODUCTS%20Highly%20expressed')
32. AnnotationURLCitation(end_index=12350, start_index=12155, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=the%20SH3%20domain%29%20%28PubMed%3A19798448%29,ALTERNATIVE%20PRODUCTS%20Highly%20expressed')
33. AnnotationURLCitation(end_index=12718, start_index=12563, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=Generation%20of%20several%20of%20the,in%20chromosome%202%20in%20humans')
34. AnnotationURLCitation(end_index=12894, start_index=12719, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=formation%20of%20actin%E2%80%90rich%20structures%20including,A%20WIP%2FWASP%20complex%20is')
35. AnnotationURLCitation(end_index=13552, start_index=13359, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=intracellular%20motility%20of%20vaccinia%20virus,Vesicle%20surfaces%20and%20along%20actin')
36. AnnotationURLCitation(end_index=13888, start_index=13695, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=intracellular%20motility%20of%20vaccinia%20virus,Vesicle%20surfaces%20and%20along%20actin')
37. AnnotationURLCitation(end_index=14464, start_index=14330, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=WIP%20has%20been%20shown%20to,terminal%20profilin%20binding%20domain')
38. AnnotationURLCitation(end_index=14713, start_index=14579, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=WIP%20has%20been%20shown%20to,terminal%20profilin%20binding%20domain')
39. AnnotationURLCitation(end_index=15280, start_index=15146, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=WIP%20has%20been%20shown%20to,terminal%20profilin%20binding%20domain')
40. AnnotationURLCitation(end_index=15421, start_index=15281, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=molecules%20like%20the%20adaptor%20proteins,Vaduva%20et')
41. AnnotationURLCitation(end_index=15598, start_index=15464, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=WIP%20has%20been%20shown%20to,terminal%20profilin%20binding%20domain')
42. AnnotationURLCitation(end_index=16047, start_index=15912, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L148%20is%20the,Invadopodia%20protein')
43. AnnotationURLCitation(end_index=16347, start_index=16213, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=WIP%20has%20been%20shown%20to,terminal%20profilin%20binding%20domain')
44. AnnotationURLCitation(end_index=16515, start_index=16381, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=WIP%20has%20been%20shown%20to,terminal%20profilin%20binding%20domain')
45. AnnotationURLCitation(end_index=16922, start_index=16715, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=intracellular%20motility%20of%20vaccinia%20virus,spleen%2C%20placenta%2C%20small%20intestine%2C%20colon')
46. AnnotationURLCitation(end_index=17413, start_index=17206, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=intracellular%20motility%20of%20vaccinia%20virus,spleen%2C%20placenta%2C%20small%20intestine%2C%20colon')
47. AnnotationURLCitation(end_index=17639, start_index=17499, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=molecules%20like%20the%20adaptor%20proteins,Vaduva%20et')
48. AnnotationURLCitation(end_index=18365, start_index=18280, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=N,These%20mutations')
49. AnnotationURLCitation(end_index=18924, start_index=18802, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%20is%20not%20necessary%20for,2002')
50. AnnotationURLCitation(end_index=19070, start_index=18925, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=appropriate%20immunological%20synapse%20formation%20and,2002')
51. AnnotationURLCitation(end_index=19456, start_index=19267, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%E2%80%90deficient%20mice%20present%20impaired%20T%E2%80%90cell,in%20both%20T%20and%20B%E2%80%90cells')
52. AnnotationURLCitation(end_index=19746, start_index=19592, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%E2%80%90deficient%20mice%20present%20impaired%20T%E2%80%90cell,23')
53. AnnotationURLCitation(end_index=20420, start_index=20272, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=fully%20recreate%20the%20immunological%20synapse,Most%20initial')
54. AnnotationURLCitation(end_index=20733, start_index=20585, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=fully%20recreate%20the%20immunological%20synapse,Most%20initial')
55. AnnotationURLCitation(end_index=21260, start_index=21071, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%E2%80%90deficient%20mice%20present%20impaired%20T%E2%80%90cell,in%20both%20T%20and%20B%E2%80%90cells')
56. AnnotationURLCitation(end_index=21424, start_index=21261, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=be%20a%20negative%20regulator%20of,detailing%20the%20human%20phenotype%20while')
57. AnnotationURLCitation(end_index=21773, start_index=21624, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=%28Pfajfer%20et%20al,T%E2%80%90cells%20to%20localize%20WIP%20and')
58. AnnotationURLCitation(end_index=22062, start_index=21930, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=enriched%20in%20F%E2%80%90actin,2013%29%2C%20in')
59. AnnotationURLCitation(end_index=22325, start_index=22193, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=enriched%20in%20F%E2%80%90actin,2013%29%2C%20in')
60. AnnotationURLCitation(end_index=22834, start_index=22699, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L161%20on%20N%E2%80%90WASP,Ant%C3%B3n')
61. AnnotationURLCitation(end_index=23117, start_index=22982, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L161%20on%20N%E2%80%90WASP,Ant%C3%B3n')
62. AnnotationURLCitation(end_index=23563, start_index=23370, title='Reactome | UniProt:O43516 WIPF1', type='url_citation', url='https://www.reactome.org/content/schema/instance/browser/uniprot%3AO43516#:~:text=intracellular%20motility%20of%20vaccinia%20virus,Vesicle%20surfaces%20and%20along%20actin')
63. AnnotationURLCitation(end_index=24017, start_index=23832, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L170%20Actin%20regulatory,of%20short%20bowel%20syndrome%2C%20ionophore%E2%80%90mediated')
64. AnnotationURLCitation(end_index=24502, start_index=24371, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=,defect%20in%20contact%20hypersensitivity%20and')
65. AnnotationURLCitation(end_index=24657, start_index=24503, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=that%20lack%20the%20actin,from%20WIP%CE%94ABD%20mice%20had%20decreased')
66. AnnotationURLCitation(end_index=25172, start_index=24978, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L74%20related%20actin%E2%80%90dependent,group%20of%20actin%E2%80%90rich%20degradative%20cellular')
67. AnnotationURLCitation(end_index=25328, start_index=25173, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=Generation%20of%20several%20of%20the,in%20chromosome%202%20in%20humans')
68. AnnotationURLCitation(end_index=26355, start_index=26209, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=between%20these%20two%20proteins%20may,depleted%20and%20WAS%20symptoms%20present')
69. AnnotationURLCitation(end_index=26493, start_index=26356, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=This%20gene%20encodes%20a%20protein,levels%20are%20depleted%20and%20WAS')
70. AnnotationURLCitation(end_index=26716, start_index=26570, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=between%20these%20two%20proteins%20may,depleted%20and%20WAS%20symptoms%20present')
71. AnnotationURLCitation(end_index=26996, start_index=26850, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=to%20increase%20actin%20polymerization,depleted%20and%20WAS%20symptoms%20present')
72. AnnotationURLCitation(end_index=27267, start_index=27137, title='A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP | Journal of Experimental Medicine | Rockefeller University Press', type='url_citation', url='https://rupress.org/jem/article-abstract/209/1/29/40968#:~:text=%28Fig,to%20examine%20whether%20transduction%20of')
73. AnnotationURLCitation(end_index=27570, start_index=27421, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=%28Pfajfer%20et%20al,T%E2%80%90cells%20to%20localize%20WIP%20and')
74. AnnotationURLCitation(end_index=27948, start_index=27803, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=protein%20%28Pfajfer%20et%20al,Further%20study%20of%20immune')
75. AnnotationURLCitation(end_index=28482, start_index=28352, title='A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP | Journal of Experimental Medicine | Rockefeller University Press', type='url_citation', url='https://rupress.org/jem/article-abstract/209/1/29/40968#:~:text=%28Fig,to%20examine%20whether%20transduction%20of')
76. AnnotationURLCitation(end_index=28747, start_index=28617, title='A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP | Journal of Experimental Medicine | Rockefeller University Press', type='url_citation', url='https://rupress.org/jem/article-abstract/209/1/29/40968#:~:text=%28Fig,to%20examine%20whether%20transduction%20of')
77. AnnotationURLCitation(end_index=29056, start_index=28913, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=The%20Wiskott,actin%20content%2C%20a%20disorganized%20actin')
78. AnnotationURLCitation(end_index=29812, start_index=29645, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=disease%2C%20focusing%20on%20cancer,Interestingly%2C%20a%20minority%20of%20studies')
79. AnnotationURLCitation(end_index=30157, start_index=29977, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=A%20direct%20correlation%20of%20worse,signaling%20in%20a%20myocardin%E2%80%90dependent%20manner')
80. AnnotationURLCitation(end_index=30333, start_index=30158, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L563%20between%20WIP,tumorigenesis%2C%20like%20stabilization%20of%20YAP%2FTAZ')
81. AnnotationURLCitation(end_index=30689, start_index=30509, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=A%20direct%20correlation%20of%20worse,signaling%20in%20a%20myocardin%E2%80%90dependent%20manner')
82. AnnotationURLCitation(end_index=31043, start_index=30858, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=A%20direct%20correlation%20of%20worse,proliferative%20ability%2C%20migration%2C%20and%20invasiveness')
83. AnnotationURLCitation(end_index=31352, start_index=31197, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=et%20al,proliferative%20ability%2C%20migration%2C%20and%20invasiveness')
84. AnnotationURLCitation(end_index=31776, start_index=31626, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=prognosis%20%28Korman%20et%20al,human%20NSCLC%20cell%20line%20and')
85. AnnotationURLCitation(end_index=32086, start_index=31983, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=al,NSCLC%29%20cell')
86. AnnotationURLCitation(end_index=32239, start_index=32087, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=In%20a%20lung%20adenocarcinoma%20cell,basal%20BC%20cell%20line%20in')
87. AnnotationURLCitation(end_index=32485, start_index=32330, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=et%20al,proliferative%20ability%2C%20migration%2C%20and%20invasiveness')
88. AnnotationURLCitation(end_index=32875, start_index=32748, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=To%20invade%20and%20migrate%20through,2016')
89. AnnotationURLCitation(end_index=33073, start_index=32876, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=For%20effective%20proteolysis%20of%20the,transcriptional%20activator%20E26%20transformation%20specific%E2%80%901')
90. AnnotationURLCitation(end_index=33347, start_index=33220, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=To%20invade%20and%20migrate%20through,2016')
91. AnnotationURLCitation(end_index=33765, start_index=33568, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=For%20effective%20proteolysis%20of%20the,transcriptional%20activator%20E26%20transformation%20specific%E2%80%901')
92. AnnotationURLCitation(end_index=33901, start_index=33766, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L148%20is%20the,Invadopodia%20protein')
93. AnnotationURLCitation(end_index=34515, start_index=34390, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=Another%20lncRNA%20reported%20to%20be,62')
94. AnnotationURLCitation(end_index=34691, start_index=34516, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=miR%E2%80%90141%20and%2C%20to%20a%20lesser,correlated%20significantly%20with%20longer%20OS')
95. AnnotationURLCitation(end_index=35137, start_index=34962, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L563%20between%20WIP,tumorigenesis%2C%20like%20stabilization%20of%20YAP%2FTAZ')
96. AnnotationURLCitation(end_index=35453, start_index=35295, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=was%20a%20gene%20directly%20associated,identified%20WIPF1%20as%20a%20gene')
97. AnnotationURLCitation(end_index=35620, start_index=35454, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=proteomics%2C%20is%20correlated%20with%20a,disease%20and%20shorter%20patient%20OS')
98. AnnotationURLCitation(end_index=35999, start_index=35832, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=disease%2C%20focusing%20on%20cancer,Interestingly%2C%20a%20minority%20of%20studies')
99. AnnotationURLCitation(end_index=36853, start_index=36703, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=prognosis%20%28Korman%20et%20al,human%20NSCLC%20cell%20line%20and')
100. AnnotationURLCitation(end_index=37350, start_index=37161, title='Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40821124/#:~:text=Successful%20placental%20development%20and%20pregnancy,involvement%20in%20successful%20placental%20development')
101. AnnotationURLCitation(end_index=37492, start_index=37351, title='Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40821124/#:~:text=exclusively%20expressed%20in%20first,derived%20EVTs%20hampered')
102. AnnotationURLCitation(end_index=37983, start_index=37842, title='Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40821124/#:~:text=exclusively%20expressed%20in%20first,derived%20EVTs%20hampered')
103. AnnotationURLCitation(end_index=38450, start_index=38261, title='Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40821124/#:~:text=Successful%20placental%20development%20and%20pregnancy,involvement%20in%20successful%20placental%20development')
104. AnnotationURLCitation(end_index=38592, start_index=38451, title='Unraveling the role of the WIPF1/ACTN4 complex in podosome formation of human placental EVTs: Insights into recurrent spontaneous abortion - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/40821124/#:~:text=exclusively%20expressed%20in%20first,derived%20EVTs%20hampered')
105. AnnotationURLCitation(end_index=39238, start_index=39065, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=regulator%20of%20cancer%20cells%20redox,to%20altered%20actin%20polymerization%20dynamics')
106. AnnotationURLCitation(end_index=40275, start_index=40108, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=disease%2C%20focusing%20on%20cancer,Interestingly%2C%20a%20minority%20of%20studies')
107. AnnotationURLCitation(end_index=40576, start_index=40418, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L583%20in%20immune,date%2C%20a%20definitive%20link%20between')
108. AnnotationURLCitation(end_index=40909, start_index=40771, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=invasiveness,overexpression%20of%20WIP%20has%20mostly')
109. AnnotationURLCitation(end_index=41181, start_index=41023, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L583%20in%20immune,date%2C%20a%20definitive%20link%20between')
110. AnnotationURLCitation(end_index=41546, start_index=41379, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=disease%2C%20focusing%20on%20cancer,Interestingly%2C%20a%20minority%20of%20studies')
111. AnnotationURLCitation(end_index=41976, start_index=41801, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L563%20between%20WIP,tumorigenesis%2C%20like%20stabilization%20of%20YAP%2FTAZ')
112. AnnotationURLCitation(end_index=42163, start_index=41977, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=between%20WIP%20overexpression%20and%20worse,tumorigenesis%2C%20like%20stabilization%20of%20YAP%2FTAZ')
113. AnnotationURLCitation(end_index=42484, start_index=42329, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=overexpression%20and%20worse%20prognosis%2C%20mostly,2023%3B%20Li%20et')
114. AnnotationURLCitation(end_index=42813, start_index=42646, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=biomarker%20for%20many%20solid%20tumors,with%20potential%20impact%20on%20prognosis')
115. AnnotationURLCitation(end_index=42988, start_index=42814, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%27s%20principal%20role%20in%20lymphocytes,actin%20dynamics%20at%20the%20immunological')
116. AnnotationURLCitation(end_index=43477, start_index=43297, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=A%20direct%20correlation%20of%20worse,signaling%20in%20a%20myocardin%E2%80%90dependent%20manner')
117. AnnotationURLCitation(end_index=43860, start_index=43688, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=reduction%20of%20lung%20metastasis%20in,correlated%20significantly%20with%20longer%20OS')
118. AnnotationURLCitation(end_index=44036, start_index=43861, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=miR%E2%80%90141%20and%2C%20to%20a%20lesser,correlated%20significantly%20with%20longer%20OS')
119. AnnotationURLCitation(end_index=44426, start_index=44268, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=was%20a%20gene%20directly%20associated,identified%20WIPF1%20as%20a%20gene')
120. AnnotationURLCitation(end_index=44955, start_index=44779, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=Murine%20WIP%20deficiency%20was%20associated,and%20T%E2%80%90cell%20activation%2C%20as%20it')
121. AnnotationURLCitation(end_index=45145, start_index=44956, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%E2%80%90deficient%20mice%20present%20impaired%20T%E2%80%90cell,in%20both%20T%20and%20B%E2%80%90cells')
122. AnnotationURLCitation(end_index=46122, start_index=45990, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=enriched%20in%20F%E2%80%90actin,2013%29%2C%20in')
123. AnnotationURLCitation(end_index=46290, start_index=46123, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=biomarker%20for%20many%20solid%20tumors,with%20potential%20impact%20on%20prognosis')
124. AnnotationURLCitation(end_index=46680, start_index=46505, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=formation%20of%20actin%E2%80%90rich%20structures%20including,A%20WIP%2FWASP%20complex%20is')
125. AnnotationURLCitation(end_index=46803, start_index=46681, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%20is%20not%20necessary%20for,2002')
126. AnnotationURLCitation(end_index=47151, start_index=46996, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=overexpression%20and%20worse%20prognosis%2C%20mostly,2023%3B%20Li%20et')
127. AnnotationURLCitation(end_index=47564, start_index=47397, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=disease%2C%20focusing%20on%20cancer,Interestingly%2C%20a%20minority%20of%20studies')
128. AnnotationURLCitation(end_index=47720, start_index=47565, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=et%20al,proliferative%20ability%2C%20migration%2C%20and%20invasiveness')
129. AnnotationURLCitation(end_index=49493, start_index=49335, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=match%20at%20L583%20in%20immune,date%2C%20a%20definitive%20link%20between')
130. AnnotationURLCitation(end_index=49668, start_index=49494, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=WIP%27s%20principal%20role%20in%20lymphocytes,actin%20dynamics%20at%20the%20immunological')
131. AnnotationURLCitation(end_index=50047, start_index=49934, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=,interacting%20protein%20family%2C%20member%201')
132. AnnotationURLCitation(end_index=50368, start_index=50222, title='WIPF1', type='url_citation', url='https://en.wikipedia.org/wiki/WIPF1#:~:text=between%20these%20two%20proteins%20may,depleted%20and%20WAS%20symptoms%20present')
133. AnnotationURLCitation(end_index=50499, start_index=50369, title='A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP | Journal of Experimental Medicine | Rockefeller University Press', type='url_citation', url='https://rupress.org/jem/article-abstract/209/1/29/40968#:~:text=%28Fig,to%20examine%20whether%20transduction%20of')
134. AnnotationURLCitation(end_index=50823, start_index=50680, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=The%20Wiskott,actin%20content%2C%20a%20disorganized%20actin')
135. AnnotationURLCitation(end_index=50978, start_index=50824, title='Binding of WIP to Actin Is Essential for T Cell Actin Cytoskeleton Integrity and Tissue Homing - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC4248745/#:~:text=that%20lack%20the%20actin,from%20WIP%CE%94ABD%20mice%20had%20decreased')
136. AnnotationURLCitation(end_index=51323, start_index=51138, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=A%20direct%20correlation%20of%20worse,proliferative%20ability%2C%20migration%2C%20and%20invasiveness')
137. AnnotationURLCitation(end_index=51689, start_index=51530, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=Cancer%20cells%20depend%20on%20actin,and%20its%20contribution%20to%20human')
138. AnnotationURLCitation(end_index=51857, start_index=51690, title='Multifaceted role of the actin‐binding protein WIP: Promotor and inhibitor of tumor progression and dissemination - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC11904860/#:~:text=disease%2C%20focusing%20on%20cancer,Interestingly%2C%20a%20minority%20of%20studies')