FERMT2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0007160 cell-matrix adhesion	IBA GO_REF:0000033	ACCEPT	Summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core. Reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
GO:0005178 integrin binding	IBA GO_REF:0000033	ACCEPT	Summary: Direct binding of the membrane-distal NPxY region of integrin beta (ITGB1/ITGB3) cytoplasmic tails is kindlin-2's signature molecular activity and the basis of co-activation with talin. Reason: Integrin-tail binding is the defining molecular function of kindlin-2.
GO:0005925 focal adhesion	IBA GO_REF:0000033	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0001725 stress fiber	IEA GO_REF:0000120	ACCEPT	Summary: Co-localizes with actin stress fibers at cell-ECM focal adhesion sites, reflecting the physical link kindlin-2 establishes between integrin adhesions and the contractile cytoskeleton. Reason: Stress-fiber association reflects the core integrin-to-actin linkage.
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Nuclear localization underlies kindlin-2's moonlighting role in Wnt/beta-catenin transcriptional regulation; distinct from its principal cytoplasmic focal-adhesion function. Reason: Secondary nuclear/transcriptional role, separate from the core integrin-adhesion function.
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions. Reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
GO:0005856 cytoskeleton	IEA GO_REF:0000044	ACCEPT	Summary: Cytoskeletal localization reflects kindlin-2 association with the actin network at adhesion sites, consistent with its integrin-to-cytoskeleton linker function. Reason: Cytoskeletal association supports the core integrin-actin linkage role.
GO:0005925 focal adhesion	IEA GO_REF:0000044	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0005938 cell cortex	IEA GO_REF:0000044	ACCEPT	Summary: Cytoplasmic, cell-cortex localization (peripheral membrane, cytoplasmic side) is where kindlin-2 engages integrin tails and the submembranous actin network at adhesion sites. Reason: Cortical/submembranous localization is intrinsic to its membrane-proximal integrin-adapter action.
GO:0007229 integrin-mediated signaling pathway	IEA GO_REF:0000002	ACCEPT	Summary: Initiates/propagates integrin-mediated (inside-out and outside-in) signaling through integrin-tail engagement and adhesome assembly; a core signaling process for kindlin-2. Reason: Integrin signaling is a core pathway directly engaged by kindlin-2.
GO:0009986 cell surface	IEA GO_REF:0000044	MODIFY	Summary: Kindlin-2 is a cytoplasmic peripheral-membrane protein acting on the inner leaflet; 'cell surface' (extracellular face, IEA) misplaces it. The accurate site is the cytoplasmic side of the plasma membrane. Reason: IEA 'cell surface' implies extracellular face; kindlin-2 is cytoplasmic, on the inner membrane leaflet. Proposed replacements: cytoplasmic side of plasma membrane
GO:0016020 membrane	IEA GO_REF:0000044	ACCEPT	Summary: Peripheral membrane association (cytoplasmic side) via PH-domain phosphoinositide and N-terminal lipid binding underlies kindlin-2's membrane-proximal integrin engagement. Reason: Membrane association via lipid binding is integral to membrane-proximal integrin activation.
GO:0030335 positive regulation of cell migration	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Promotes cell migration (IMP), a downstream behavior enabled by kindlin-2-driven focal-adhesion dynamics and integrin activation rather than a defining molecular function. Reason: Migration is a downstream cellular behavior of the integrin-adhesion core.
GO:0031258 lamellipodium membrane	IEA GO_REF:0000044	ACCEPT	Summary: Kindlin-2 co-localizes with ITGB3 at lamellipodia at the leading edge of spreading cells, a membrane site directly tied to integrin activation during spreading. Reason: Leading-edge membrane localization is part of its integrin-activation/spreading role.
GO:0031674 I band	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Sarcomeric I-band localization (ISS to mouse) reflects kindlin-2 at the myotendinous/costameric integrin adhesions of striated muscle, a tissue-specific context of its adhesion role rather than its defining site. Reason: Muscle-specific localization downstream of the core integrin-adhesion adapter function; not the primary site of action.
GO:0005515 protein binding	IPI PMID:22699938 Kindlin 2 forms a transcriptional complex with β-catenin and...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (IPI) is uninformative for an adapter with many defined partners (integrins, FBLIM1, ILK, CTNNB1); specific binding terms already capture the meaningful interactions. Reason: Generic uninformative MF; specific partner-binding terms are preferable.
GO:0007160 cell-matrix adhesion	IEA GO_REF:0000107	ACCEPT	Summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core. Reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
GO:0033622 integrin activation	IEA GO_REF:0000107	ACCEPT	Summary: Co-activates integrins with talin: binding the membrane-distal beta-tail NPxY motif, kindlin-2 enhances affinity maturation; QW614-615AA abolishes ITGB3 binding and activation enhancement. Reason: Integrin (co-)activation is the central molecular process defining kindlin-2.
GO:0034334 adherens junction maintenance	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Kindlin-2 contributes to maintaining adherens junctions, a downstream tissue-integrity role distinct from its proximal integrin/focal-adhesion adapter activity. Reason: Downstream junction-maintenance process, not the proximal integrin-adhesion function.
GO:0034446 substrate adhesion-dependent cell spreading	IEA GO_REF:0000107	ACCEPT	Summary: Mediates substrate adhesion-dependent cell spreading (ISS); kindlin-2 enhancement of ECM adhesion and lamellipodial integrin engagement drives cell spreading. Reason: Substrate-dependent spreading is a core process driven by kindlin-2 adhesion activity.
GO:0043116 negative regulation of vascular permeability	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Reduces vascular permeability (IMP) via endothelial adhesion/junction integrity, a physiological consequence of kindlin-2 adhesion function rather than its proximal molecular role. Reason: Endothelial-barrier phenotype downstream of the core adhesion role.
GO:0045599 negative regulation of fat cell differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Inhibits adipocyte differentiation (IMP), a cell-fate output of kindlin-2 adhesion/signaling crosstalk, downstream and tissue-specific relative to the integrin-adapter core. Reason: Cell-differentiation output downstream of adhesion signaling, not the core function.
GO:0045669 positive regulation of osteoblast differentiation	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Promotes osteoblast differentiation (IMP), a skeletal cell-fate output linked to integrin/fibronectin adhesion; downstream and tissue-specific relative to the adapter core. Reason: Tissue-specific differentiation output downstream of integrin adhesion.
GO:0048041 focal adhesion assembly	IEA GO_REF:0000107	ACCEPT	Summary: Kindlin-2 is required for focal-adhesion assembly; its integrin co-activation nucleates the adhesion complex, a core process supported by IMP/ISS evidence. Reason: Focal-adhesion assembly is a core process requiring kindlin-2.
GO:0051015 actin filament binding	IEA GO_REF:0000107	ACCEPT	Summary: Binding actin filaments anchors integrin adhesion complexes to the contractile cytoskeleton, supporting kindlin-2's role linking focal adhesions to stress fibers. Reason: Specific cytoskeletal-binding activity supporting the core integrin-actin linker role.
GO:0060173 limb development	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Limb development (IEA) is an organismal phenotype downstream of kindlin-2-dependent integrin adhesion in developing tissues; a developmental consequence, not the molecular core. Reason: Organ-development phenotype downstream of the integrin-adhesion adapter role.
GO:0072657 protein localization to membrane	IEA GO_REF:0000107	ACCEPT	Summary: Recruits/retains partners at the plasma membrane (ISS) as part of assembling the membrane-proximal integrin adhesion complex; integral to kindlin-2's scaffolding role. Reason: Membrane recruitment of adhesome partners is part of the core scaffolding function.
GO:0005654 nucleoplasm	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Nucleoplasmic localization (IDA/HPA) reflects the moonlighting nuclear pool involved in CTNNB1/TCF-mediated transcription; peripheral to the core adhesion role. Reason: Nuclear pool serving moonlighting transcriptional crosstalk, not the adhesion core.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Cytosolic pool (IDA/TAS) of kindlin-2 before/while it is recruited to membrane adhesion sites; consistent with a soluble cytoplasmic adapter. Reason: Soluble cytosolic pool of a cytoplasmic adhesion adapter.
GO:0005925 focal adhesion	IDA GO_REF:0000052	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0035025 positive regulation of Rho protein signal transduction	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	ACCEPT	Summary: Positively regulates Rho-family signaling (IMP) emanating from adhesion sites, coupling kindlin-2-mediated integrin engagement to actomyosin/stress-fiber regulation. Reason: Adhesion-coupled Rho signaling is integral to the integrin-to-cytoskeleton core role.
GO:0043539 protein serine/threonine kinase activator activity	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	KEEP AS NON CORE	Summary: Reported activation of a Ser/Thr kinase (IMP) is a context-specific signaling output downstream of kindlin-2 adhesion scaffolding, not a defining enzymatic-partner activity. Reason: Downstream kinase-activation output, secondary to the integrin-adapter core.
GO:0120283 protein serine/threonine kinase binding	IPI PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	KEEP AS NON CORE	Summary: Binding a Ser/Thr kinase (IPI), e.g. in TGF-beta-receptor-associated signaling, is a specific secondary partner interaction peripheral to the integrin-adhesion function. Reason: Specific kinase-partner binding tied to secondary signaling, not the adhesion core.
GO:0005515 protein binding	IPI PMID:25160619 Molecular basis of kindlin-2 binding to integrin-linked kina...	MARK AS OVER ANNOTATED	Summary: Bare 'protein binding' (IPI) is uninformative for an adapter with many defined partners (integrins, FBLIM1, ILK, CTNNB1); specific binding terms already capture the meaningful interactions. Reason: Generic uninformative MF; specific partner-binding terms are preferable.
GO:0009898 cytoplasmic side of plasma membrane	IDA PMID:21325030 Kindlin-2 regulates podocyte adhesion and fibronectin matrix...	ACCEPT	Summary: Localizes to the cytoplasmic face of the plasma membrane (IDA), where it binds inner-leaflet phosphoinositides and integrin beta cytoplasmic tails; the precise site of its core action. Reason: Inner-leaflet membrane localization is the precise site of integrin-tail/PIP binding.
GO:0007155 cell adhesion	IGI PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce...	ACCEPT	Summary: Kindlin-2 is required for integrin-mediated cell adhesion to the ECM (IGI/IMP); a core process directly arising from its integrin co-activation and focal-adhesion assembly activities. Reason: Cell adhesion is a core process directly mediated by kindlin-2.
GO:1900026 positive regulation of substrate adhesion-dependent cell spreading	IGI PMID:30254023 Kindlin-2 interacts with a highly conserved surface of ILK t...	ACCEPT	Summary: Promotes substrate-dependent cell spreading (IGI), requiring both integrin and phospholipid binding; a direct readout of kindlin-2 integrin co-activation at the leading edge. Reason: Spreading promotion is a direct core consequence of integrin co-activation.
GO:0033625 positive regulation of integrin activation	IGI PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce...	ACCEPT	Summary: Positively regulates integrin activation by cooperating with talin at the beta-tail (IGI), the directional core activity by which kindlin-2 promotes integrin affinity. Reason: Positive integrin-activation regulation is the core kindlin-2 function.
GO:0048041 focal adhesion assembly	IMP PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce...	ACCEPT	Summary: Kindlin-2 is required for focal-adhesion assembly; its integrin co-activation nucleates the adhesion complex, a core process supported by IMP/ISS evidence. Reason: Focal-adhesion assembly is a core process requiring kindlin-2.
GO:1903691 positive regulation of wound healing, spreading of epidermal cells	IMP PMID:21356350 Kindlin-1 and -2 have overlapping functions in epithelial ce...	KEEP AS NON CORE	Summary: Promotes epidermal-cell spreading in wound healing (IMP), an organismal/tissue phenotype downstream of kindlin-2-driven integrin adhesion and cell spreading. Reason: Wound-healing tissue phenotype downstream of the adhesion/spreading core.
GO:0005737 cytoplasm	IDA PMID:28799653 Kindlin-2 interacts with endothelial adherens junctions to s...	ACCEPT	Summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions. Reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
GO:0005912 adherens junction	IDA PMID:28799653 Kindlin-2 interacts with endothelial adherens junctions to s...	KEEP AS NON CORE	Summary: Adherens-junction localization (IDA) reflects kindlin-2 at cell-cell adhesion sites in some epithelial contexts; secondary to its principal cell-matrix focal-adhesion localization. Reason: Cell-cell junction context is secondary to the core cell-matrix focal-adhesion site.
GO:0034334 adherens junction maintenance	IMP PMID:28799653 Kindlin-2 interacts with endothelial adherens junctions to s...	KEEP AS NON CORE	Summary: Kindlin-2 contributes to maintaining adherens junctions, a downstream tissue-integrity role distinct from its proximal integrin/focal-adhesion adapter activity. Reason: Downstream junction-maintenance process, not the proximal integrin-adhesion function.
GO:0043116 negative regulation of vascular permeability	IMP PMID:28799653 Kindlin-2 interacts with endothelial adherens junctions to s...	KEEP AS NON CORE	Summary: Reduces vascular permeability (IMP) via endothelial adhesion/junction integrity, a physiological consequence of kindlin-2 adhesion function rather than its proximal molecular role. Reason: Endothelial-barrier phenotype downstream of the core adhesion role.
GO:0005737 cytoplasm	IDA PMID:18528435 Colocalization of kindlin-1, kindlin-2, and migfilin at kera...	ACCEPT	Summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions. Reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
GO:0005925 focal adhesion	IDA PMID:18528435 Colocalization of kindlin-1, kindlin-2, and migfilin at kera...	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0010718 positive regulation of epithelial to mesenchymal transition	IDA PMID:24226523 Kindlin-2 regulates renal tubular cell plasticity by activat...	KEEP AS NON CORE	Summary: Promotes EMT (IDA), likely via TGF-beta/Wnt crosstalk; a pleiotropic cell-state transition downstream of kindlin-2 adhesion and signaling roles. Reason: EMT promotion is downstream pleiotropic crosstalk, not the adhesion core.
GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	IDA PMID:24226523 Kindlin-2 regulates renal tubular cell plasticity by activat...	KEEP AS NON CORE	Summary: Promotes PI3K/AKT signaling (IDA), a downstream survival/growth cascade activated through integrin adhesion; a secondary signaling output of kindlin-2. Reason: Downstream PI3K/AKT signaling output of the adhesion core, not the proximal function.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IDA PMID:24226523 Kindlin-2 regulates renal tubular cell plasticity by activat...	KEEP AS NON CORE	Summary: Promotes ERK1/2 signaling (IDA) as a downstream consequence of integrin-mediated adhesion signaling; a secondary signaling output of the adhesion core. Reason: Downstream MAPK output of adhesion signaling, not the proximal adapter function.
GO:0005829 cytosol	IDA PMID:23723426 Kindlin-2 mediates activation of TGF-β/Smad signaling and re...	ACCEPT	Summary: Cytosolic pool (IDA/TAS) of kindlin-2 before/while it is recruited to membrane adhesion sites; consistent with a soluble cytoplasmic adapter. Reason: Soluble cytosolic pool of a cytoplasmic adhesion adapter.
GO:0005886 plasma membrane	IDA PMID:23723426 Kindlin-2 mediates activation of TGF-β/Smad signaling and re...	ACCEPT	Summary: Plasma-membrane localization (IDA) is where kindlin-2 binds integrin beta tails and inner-leaflet phosphoinositides; consistent with its membrane-proximal adapter role. Reason: Plasma-membrane localization is core to integrin-tail and lipid engagement.
GO:0034713 type I transforming growth factor beta receptor binding	IPI PMID:23723426 Kindlin-2 mediates activation of TGF-β/Smad signaling and re...	KEEP AS NON CORE	Summary: Binding the type I TGF-beta receptor (IPI) supports kindlin-2's modulation of TGF-beta/SMAD signaling; a specific partner in a pleiotropic pathway, not the adhesion core. Reason: Specific TGF-beta receptor partner underlying pleiotropic signaling, peripheral to adhesion.
GO:0046332 SMAD binding	IPI PMID:23723426 Kindlin-2 mediates activation of TGF-β/Smad signaling and re...	KEEP AS NON CORE	Summary: SMAD binding (IPI) underlies kindlin-2 participation in TGF-beta/SMAD crosstalk; a secondary signaling partner, peripheral to its integrin-adapter core. Reason: Pleiotropic TGF-beta signaling partner, not part of the proximal integrin-adhesion function.
GO:1900182 positive regulation of protein localization to nucleus	IDA PMID:23723426 Kindlin-2 mediates activation of TGF-β/Smad signaling and re...	KEEP AS NON CORE	Summary: Promotes nuclear localization of a partner (e.g. beta-catenin, IDA), part of kindlin-2's moonlighting transcriptional role; distinct from its cytoplasmic adhesion function. Reason: Nuclear-trafficking role tied to moonlighting transcription, peripheral to adhesion.
GO:0003779 actin binding	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	ACCEPT	Summary: Kindlin-2 binds actin, contributing to the physical connection between integrin-based ECM adhesion sites and the actin cytoskeleton; central to its cytoskeletal-linker adapter role. Reason: Direct actin binding is part of the defining integrin-to-actin linkage function.
GO:0005925 focal adhesion	IDA PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0019901 protein kinase binding	IPI PMID:30254023 Kindlin-2 interacts with a highly conserved surface of ILK t...	ACCEPT	Summary: Kindlin-2 binds protein kinase partners (e.g. ILK within the kindlin-ILK-PINCH/IPP focal-adhesion complex), a specific interaction central to assembling the integrin adhesome. Reason: Specific kinase (ILK/adhesome) binding is part of the core focal-adhesion scaffolding role.
GO:0022604 regulation of cell morphogenesis	IMP PMID:30254023 Kindlin-2 interacts with a highly conserved surface of ILK t...	ACCEPT	Summary: Regulates cell morphogenesis/shape (IMP) via orchestration of actin assembly at integrin adhesions; cell-shape modulation is an intrinsic part of kindlin-2's described function. Reason: Cell-shape/morphogenesis modulation is an intrinsic core kindlin-2 function.
GO:0045599 negative regulation of fat cell differentiation	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	KEEP AS NON CORE	Summary: Inhibits adipocyte differentiation (IMP), a cell-fate output of kindlin-2 adhesion/signaling crosstalk, downstream and tissue-specific relative to the integrin-adapter core. Reason: Cell-differentiation output downstream of adhesion signaling, not the core function.
GO:0045669 positive regulation of osteoblast differentiation	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	KEEP AS NON CORE	Summary: Promotes osteoblast differentiation (IMP), a skeletal cell-fate output linked to integrin/fibronectin adhesion; downstream and tissue-specific relative to the adapter core. Reason: Tissue-specific differentiation output downstream of integrin adhesion.
GO:0051496 positive regulation of stress fiber assembly	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	ACCEPT	Summary: Promotes stress-fiber assembly (IMP) by coupling integrin adhesions to actin, reflecting kindlin-2's integrin-to-cytoskeleton linkage and cell-shape modulation. Reason: Stress-fiber promotion follows directly from the integrin-actin linker role.
GO:0051894 positive regulation of focal adhesion assembly	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	ACCEPT	Summary: Promotes focal-adhesion assembly (IMP) as a direct consequence of kindlin-2-driven integrin activation and adhesome recruitment; a core adhesion process. Reason: Promoting focal-adhesion assembly is part of the core adhesion function.
GO:1902414 protein localization to cell junction	IMP PMID:30254023 Kindlin-2 interacts with a highly conserved surface of ILK t...	KEEP AS NON CORE	Summary: Targets partner proteins (e.g. FBLIM1) to adhesion junctions (IMP); a specific recruitment activity supporting, but downstream of, the proximal integrin-adapter role. Reason: Partner-recruitment-to-junction activity downstream of the core scaffolding function.
GO:1902462 positive regulation of mesenchymal stem cell proliferation	IMP PMID:29496737 Kindlin-2 regulates mesenchymal stem cell differentiation th...	KEEP AS NON CORE	Summary: Promotes MSC proliferation (IMP), a cell-type-specific growth output of kindlin-2 adhesion/signaling activity, downstream of its proximal integrin-adapter role. Reason: Cell-type-specific proliferation output downstream of adhesion function.
GO:0005886 plasma membrane	IDA PMID:30382829 Fermitin family homolog-2 (FERMT2) is highly expressed in hu...	ACCEPT	Summary: Plasma-membrane localization (IDA) is where kindlin-2 binds integrin beta tails and inner-leaflet phosphoinositides; consistent with its membrane-proximal adapter role. Reason: Plasma-membrane localization is core to integrin-tail and lipid engagement.
GO:0007155 cell adhesion	IMP PMID:30382829 Fermitin family homolog-2 (FERMT2) is highly expressed in hu...	ACCEPT	Summary: Kindlin-2 is required for integrin-mediated cell adhesion to the ECM (IGI/IMP); a core process directly arising from its integrin co-activation and focal-adhesion assembly activities. Reason: Cell adhesion is a core process directly mediated by kindlin-2.
GO:0030054 cell junction	IDA PMID:30382829 Fermitin family homolog-2 (FERMT2) is highly expressed in hu...	KEEP AS NON CORE	Summary: Generic cell-junction localization (IDA); kindlin-2's specific and defining junction is the cell-matrix focal adhesion, captured by more precise terms. Reason: Generic junction term subsumed by the specific focal-adhesion localization.
GO:0030335 positive regulation of cell migration	IMP PMID:30382829 Fermitin family homolog-2 (FERMT2) is highly expressed in hu...	KEEP AS NON CORE	Summary: Promotes cell migration (IMP), a downstream behavior enabled by kindlin-2-driven focal-adhesion dynamics and integrin activation rather than a defining molecular function. Reason: Migration is a downstream cellular behavior of the integrin-adhesion core.
GO:0005925 focal adhesion	IDA PMID:29162887 The WD40-domain containing protein CORO2B is specifically en...	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0005925 focal adhesion	HDA PMID:21423176 Analysis of the myosin-II-responsive focal adhesion proteome...	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0005829 cytosol	TAS Reactome:R-HSA-430341	ACCEPT	Summary: Cytosolic pool (IDA/TAS) of kindlin-2 before/while it is recruited to membrane adhesion sites; consistent with a soluble cytoplasmic adapter. Reason: Soluble cytosolic pool of a cytoplasmic adhesion adapter.
GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding	IDA PMID:21325030 Kindlin-2 regulates podocyte adhesion and fibronectin matrix...	ACCEPT	Summary: The PH domain binds PIP3 preferentially (NMR structure, PMID:22030399); K383/K385 mutations reduce lipid binding and integrin activation, making this lipid-binding activity core to membrane targeting. Reason: PH-domain PIP3 binding is mechanistically required for membrane-proximal integrin activation.
GO:0005634 nucleus	IDA PMID:22699938 Kindlin 2 forms a transcriptional complex with β-catenin and...	KEEP AS NON CORE	Summary: Nuclear localization underlies kindlin-2's moonlighting role in Wnt/beta-catenin transcriptional regulation; distinct from its principal cytoplasmic focal-adhesion function. Reason: Secondary nuclear/transcriptional role, separate from the core integrin-adhesion function.
GO:0005737 cytoplasm	IDA PMID:22699938 Kindlin 2 forms a transcriptional complex with β-catenin and...	ACCEPT	Summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions. Reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
GO:0005925 focal adhesion	IDA PMID:21325030 Kindlin-2 regulates podocyte adhesion and fibronectin matrix...	ACCEPT	Summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1. Reason: Focal adhesion is the central, defining localization of kindlin-2.
GO:0007160 cell-matrix adhesion	IMP PMID:21325030 Kindlin-2 regulates podocyte adhesion and fibronectin matrix...	ACCEPT	Summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core. Reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
GO:0007179 transforming growth factor beta receptor signaling pathway	IMP PMID:21325030 Kindlin-2 regulates podocyte adhesion and fibronectin matrix...	KEEP AS NON CORE	Summary: Participates in TGF-beta receptor signaling (IMP) via receptor/SMAD interactions; a pleiotropic signaling role distinct from the integrin-adhesion core. Reason: Pleiotropic TGF-beta signaling role, separate from the core adhesion function.
GO:0007229 integrin-mediated signaling pathway	IMP PMID:21325030 Kindlin-2 regulates podocyte adhesion and fibronectin matrix...	ACCEPT	Summary: Initiates/propagates integrin-mediated (inside-out and outside-in) signaling through integrin-tail engagement and adhesome assembly; a core signaling process for kindlin-2. Reason: Integrin signaling is a core pathway directly engaged by kindlin-2.
GO:0016055 Wnt signaling pathway	IMP PMID:22699938 Kindlin 2 forms a transcriptional complex with β-catenin and...	KEEP AS NON CORE	Summary: Kindlin-2 stabilizes active CTNNB1 and forms a complex with CTNNB1/TCF7L2 to enhance Wnt-driven transcription (PMID:22699938); a moonlighting nuclear role distinct from focal-adhesion adhesion. Reason: Nuclear Wnt/beta-catenin crosstalk is a pleiotropic moonlighting role, not the core adhesion function.
GO:0005547 phosphatidylinositol-3,4,5-trisphosphate binding	IDA PMID:22030399 Structural basis of phosphoinositide binding to kindlin-2 pr...	ACCEPT	Summary: The PH domain binds PIP3 preferentially (NMR structure, PMID:22030399); K383/K385 mutations reduce lipid binding and integrin activation, making this lipid-binding activity core to membrane targeting. Reason: PH-domain PIP3 binding is mechanistically required for membrane-proximal integrin activation.
GO:0007160 cell-matrix adhesion	ISS GO_REF:0000024	ACCEPT	Summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core. Reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
GO:0033622 integrin activation	IMP PMID:22030399 Structural basis of phosphoinositide binding to kindlin-2 pr...	ACCEPT	Summary: Co-activates integrins with talin: binding the membrane-distal beta-tail NPxY motif, kindlin-2 enhances affinity maturation; QW614-615AA abolishes ITGB3 binding and activation enhancement. Reason: Integrin (co-)activation is the central molecular process defining kindlin-2.
GO:0034446 substrate adhesion-dependent cell spreading	ISS GO_REF:0000024	ACCEPT	Summary: Mediates substrate adhesion-dependent cell spreading (ISS); kindlin-2 enhancement of ECM adhesion and lamellipodial integrin engagement drives cell spreading. Reason: Substrate-dependent spreading is a core process driven by kindlin-2 adhesion activity.
GO:0048041 focal adhesion assembly	ISS GO_REF:0000024	ACCEPT	Summary: Kindlin-2 is required for focal-adhesion assembly; its integrin co-activation nucleates the adhesion complex, a core process supported by IMP/ISS evidence. Reason: Focal-adhesion assembly is a core process requiring kindlin-2.
GO:0072657 protein localization to membrane	ISS GO_REF:0000024	ACCEPT	Summary: Recruits/retains partners at the plasma membrane (ISS) as part of assembling the membrane-proximal integrin adhesion complex; integral to kindlin-2's scaffolding role. Reason: Membrane recruitment of adhesome partners is part of the core scaffolding function.

📄 View Raw YAML

id: Q96AC1
gene_symbol: FERMT2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 'FERMT2 encodes kindlin-2, a broadly expressed FERM/PH domain-containing adaptor that localizes to focal adhesions, the cytoplasmic side of membranes, cytoskeleton, cell cortex, and related adhesion structures. Kindlin-2 binds integrin cytoplasmic tails and phosphoinositide-rich membranes, cooperates with talin to promote integrin activation, and links cell-extracellular matrix adhesions to focal adhesion assembly, actin organization, cell spreading, and cell-shape control. It also participates in context-specific signaling branches including Wnt/beta-catenin, TGF-beta/Smad, adherens-junction vascular barrier regulation, and mesenchymal stem-cell fate control.'
alternative_products:
- name: '1'
  id: Q96AC1-1
- name: '2'
  id: Q96AC1-2
  sequence_note: VSP_008783, VSP_008784, VSP_008785
- name: '3'
  id: Q96AC1-3
  sequence_note: VSP_008783
existing_annotations:
- term:
    id: GO:0007160
    label: cell-matrix adhesion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core.
    action: ACCEPT
    reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
- term:
    id: GO:0005178
    label: integrin binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Direct binding of the membrane-distal NPxY region of integrin beta (ITGB1/ITGB3) cytoplasmic tails is kindlin-2's signature molecular activity and the basis of co-activation with talin.
    action: ACCEPT
    reason: Integrin-tail binding is the defining molecular function of kindlin-2.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0001725
    label: stress fiber
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Co-localizes with actin stress fibers at cell-ECM focal adhesion sites, reflecting the physical link kindlin-2 establishes between integrin adhesions and the contractile cytoskeleton.
    action: ACCEPT
    reason: Stress-fiber association reflects the core integrin-to-actin linkage.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization underlies kindlin-2's moonlighting role in Wnt/beta-catenin transcriptional regulation; distinct from its principal cytoplasmic focal-adhesion function.
    action: KEEP_AS_NON_CORE
    reason: Secondary nuclear/transcriptional role, separate from the core integrin-adhesion function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions.
    action: ACCEPT
    reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
- term:
    id: GO:0005856
    label: cytoskeleton
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoskeletal localization reflects kindlin-2 association with the actin network at adhesion sites, consistent with its integrin-to-cytoskeleton linker function.
    action: ACCEPT
    reason: Cytoskeletal association supports the core integrin-actin linkage role.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0005938
    label: cell cortex
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Cytoplasmic, cell-cortex localization (peripheral membrane, cytoplasmic side) is where kindlin-2 engages integrin tails and the submembranous actin network at adhesion sites.
    action: ACCEPT
    reason: Cortical/submembranous localization is intrinsic to its membrane-proximal integrin-adapter action.
- term:
    id: GO:0007229
    label: integrin-mediated signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: Initiates/propagates integrin-mediated (inside-out and outside-in) signaling through integrin-tail engagement and adhesome assembly; a core signaling process for kindlin-2.
    action: ACCEPT
    reason: Integrin signaling is a core pathway directly engaged by kindlin-2.
- term:
    id: GO:0009986
    label: cell surface
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Kindlin-2 is a cytoplasmic peripheral-membrane protein acting on the inner leaflet; 'cell surface' (extracellular face, IEA) misplaces it. The accurate site is the cytoplasmic side of the plasma membrane.
    action: MODIFY
    reason: IEA 'cell surface' implies extracellular face; kindlin-2 is cytoplasmic, on the inner membrane leaflet.
    proposed_replacement_terms:
    - id: GO:0009898
      label: cytoplasmic side of plasma membrane
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Peripheral membrane association (cytoplasmic side) via PH-domain phosphoinositide and N-terminal lipid binding underlies kindlin-2's membrane-proximal integrin engagement.
    action: ACCEPT
    reason: Membrane association via lipid binding is integral to membrane-proximal integrin activation.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: Promotes cell migration (IMP), a downstream behavior enabled by kindlin-2-driven focal-adhesion dynamics and integrin activation rather than a defining molecular function.
    action: KEEP_AS_NON_CORE
    reason: Migration is a downstream cellular behavior of the integrin-adhesion core.
- term:
    id: GO:0031258
    label: lamellipodium membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Kindlin-2 co-localizes with ITGB3 at lamellipodia at the leading edge of spreading cells, a membrane site directly tied to integrin activation during spreading.
    action: ACCEPT
    reason: Leading-edge membrane localization is part of its integrin-activation/spreading role.
- term:
    id: GO:0031674
    label: I band
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Sarcomeric I-band localization (ISS to mouse) reflects kindlin-2 at the myotendinous/costameric integrin adhesions of striated muscle, a tissue-specific context of its adhesion role rather than its defining site.
    action: KEEP_AS_NON_CORE
    reason: Muscle-specific localization downstream of the core integrin-adhesion adapter function; not the primary site of action.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22699938
  qualifier: enables
  review:
    summary: Bare 'protein binding' (IPI) is uninformative for an adapter with many defined partners (integrins, FBLIM1, ILK, CTNNB1); specific binding terms already capture the meaningful interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic uninformative MF; specific partner-binding terms are preferable.
- term:
    id: GO:0007160
    label: cell-matrix adhesion
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core.
    action: ACCEPT
    reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
- term:
    id: GO:0033622
    label: integrin activation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'Co-activates integrins with talin: binding the membrane-distal beta-tail NPxY motif, kindlin-2 enhances affinity maturation; QW614-615AA abolishes ITGB3 binding and activation enhancement.'
    action: ACCEPT
    reason: Integrin (co-)activation is the central molecular process defining kindlin-2.
- term:
    id: GO:0034334
    label: adherens junction maintenance
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Kindlin-2 contributes to maintaining adherens junctions, a downstream tissue-integrity role distinct from its proximal integrin/focal-adhesion adapter activity.
    action: KEEP_AS_NON_CORE
    reason: Downstream junction-maintenance process, not the proximal integrin-adhesion function.
- term:
    id: GO:0034446
    label: substrate adhesion-dependent cell spreading
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Mediates substrate adhesion-dependent cell spreading (ISS); kindlin-2 enhancement of ECM adhesion and lamellipodial integrin engagement drives cell spreading.
    action: ACCEPT
    reason: Substrate-dependent spreading is a core process driven by kindlin-2 adhesion activity.
- term:
    id: GO:0043116
    label: negative regulation of vascular permeability
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Reduces vascular permeability (IMP) via endothelial adhesion/junction integrity, a physiological consequence of kindlin-2 adhesion function rather than its proximal molecular role.
    action: KEEP_AS_NON_CORE
    reason: Endothelial-barrier phenotype downstream of the core adhesion role.
- term:
    id: GO:0045599
    label: negative regulation of fat cell differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Inhibits adipocyte differentiation (IMP), a cell-fate output of kindlin-2 adhesion/signaling crosstalk, downstream and tissue-specific relative to the integrin-adapter core.
    action: KEEP_AS_NON_CORE
    reason: Cell-differentiation output downstream of adhesion signaling, not the core function.
- term:
    id: GO:0045669
    label: positive regulation of osteoblast differentiation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Promotes osteoblast differentiation (IMP), a skeletal cell-fate output linked to integrin/fibronectin adhesion; downstream and tissue-specific relative to the adapter core.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific differentiation output downstream of integrin adhesion.
- term:
    id: GO:0048041
    label: focal adhesion assembly
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Kindlin-2 is required for focal-adhesion assembly; its integrin co-activation nucleates the adhesion complex, a core process supported by IMP/ISS evidence.
    action: ACCEPT
    reason: Focal-adhesion assembly is a core process requiring kindlin-2.
- term:
    id: GO:0051015
    label: actin filament binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    summary: Binding actin filaments anchors integrin adhesion complexes to the contractile cytoskeleton, supporting kindlin-2's role linking focal adhesions to stress fibers.
    action: ACCEPT
    reason: Specific cytoskeletal-binding activity supporting the core integrin-actin linker role.
- term:
    id: GO:0060173
    label: limb development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Limb development (IEA) is an organismal phenotype downstream of kindlin-2-dependent integrin adhesion in developing tissues; a developmental consequence, not the molecular core.
    action: KEEP_AS_NON_CORE
    reason: Organ-development phenotype downstream of the integrin-adhesion adapter role.
- term:
    id: GO:0072657
    label: protein localization to membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Recruits/retains partners at the plasma membrane (ISS) as part of assembling the membrane-proximal integrin adhesion complex; integral to kindlin-2's scaffolding role.
    action: ACCEPT
    reason: Membrane recruitment of adhesome partners is part of the core scaffolding function.
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Nucleoplasmic localization (IDA/HPA) reflects the moonlighting nuclear pool involved in CTNNB1/TCF-mediated transcription; peripheral to the core adhesion role.
    action: KEEP_AS_NON_CORE
    reason: Nuclear pool serving moonlighting transcriptional crosstalk, not the adhesion core.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Cytosolic pool (IDA/TAS) of kindlin-2 before/while it is recruited to membrane adhesion sites; consistent with a soluble cytoplasmic adapter.
    action: ACCEPT
    reason: Soluble cytosolic pool of a cytoplasmic adhesion adapter.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0035025
    label: positive regulation of Rho protein signal transduction
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: involved_in
  review:
    summary: Positively regulates Rho-family signaling (IMP) emanating from adhesion sites, coupling kindlin-2-mediated integrin engagement to actomyosin/stress-fiber regulation.
    action: ACCEPT
    reason: Adhesion-coupled Rho signaling is integral to the integrin-to-cytoskeleton core role.
- term:
    id: GO:0043539
    label: protein serine/threonine kinase activator activity
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: enables
  review:
    summary: Reported activation of a Ser/Thr kinase (IMP) is a context-specific signaling output downstream of kindlin-2 adhesion scaffolding, not a defining enzymatic-partner activity.
    action: KEEP_AS_NON_CORE
    reason: Downstream kinase-activation output, secondary to the integrin-adapter core.
- term:
    id: GO:0120283
    label: protein serine/threonine kinase binding
  evidence_type: IPI
  original_reference_id: PMID:29496737
  qualifier: enables
  review:
    summary: Binding a Ser/Thr kinase (IPI), e.g. in TGF-beta-receptor-associated signaling, is a specific secondary partner interaction peripheral to the integrin-adhesion function.
    action: KEEP_AS_NON_CORE
    reason: Specific kinase-partner binding tied to secondary signaling, not the adhesion core.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25160619
  qualifier: enables
  review:
    summary: Bare 'protein binding' (IPI) is uninformative for an adapter with many defined partners (integrins, FBLIM1, ILK, CTNNB1); specific binding terms already capture the meaningful interactions.
    action: MARK_AS_OVER_ANNOTATED
    reason: Generic uninformative MF; specific partner-binding terms are preferable.
- term:
    id: GO:0009898
    label: cytoplasmic side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:21325030
  qualifier: located_in
  review:
    summary: Localizes to the cytoplasmic face of the plasma membrane (IDA), where it binds inner-leaflet phosphoinositides and integrin beta cytoplasmic tails; the precise site of its core action.
    action: ACCEPT
    reason: Inner-leaflet membrane localization is the precise site of integrin-tail/PIP binding.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IGI
  original_reference_id: PMID:21356350
  qualifier: acts_upstream_of_or_within
  review:
    summary: Kindlin-2 is required for integrin-mediated cell adhesion to the ECM (IGI/IMP); a core process directly arising from its integrin co-activation and focal-adhesion assembly activities.
    action: ACCEPT
    reason: Cell adhesion is a core process directly mediated by kindlin-2.
- term:
    id: GO:1900026
    label: positive regulation of substrate adhesion-dependent cell spreading
  evidence_type: IGI
  original_reference_id: PMID:30254023
  qualifier: involved_in
  review:
    summary: Promotes substrate-dependent cell spreading (IGI), requiring both integrin and phospholipid binding; a direct readout of kindlin-2 integrin co-activation at the leading edge.
    action: ACCEPT
    reason: Spreading promotion is a direct core consequence of integrin co-activation.
- term:
    id: GO:0033625
    label: positive regulation of integrin activation
  evidence_type: IGI
  original_reference_id: PMID:21356350
  qualifier: involved_in
  review:
    summary: Positively regulates integrin activation by cooperating with talin at the beta-tail (IGI), the directional core activity by which kindlin-2 promotes integrin affinity.
    action: ACCEPT
    reason: Positive integrin-activation regulation is the core kindlin-2 function.
- term:
    id: GO:0048041
    label: focal adhesion assembly
  evidence_type: IMP
  original_reference_id: PMID:21356350
  qualifier: involved_in
  review:
    summary: Kindlin-2 is required for focal-adhesion assembly; its integrin co-activation nucleates the adhesion complex, a core process supported by IMP/ISS evidence.
    action: ACCEPT
    reason: Focal-adhesion assembly is a core process requiring kindlin-2.
- term:
    id: GO:1903691
    label: positive regulation of wound healing, spreading of epidermal cells
  evidence_type: IMP
  original_reference_id: PMID:21356350
  qualifier: involved_in
  review:
    summary: Promotes epidermal-cell spreading in wound healing (IMP), an organismal/tissue phenotype downstream of kindlin-2-driven integrin adhesion and cell spreading.
    action: KEEP_AS_NON_CORE
    reason: Wound-healing tissue phenotype downstream of the adhesion/spreading core.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:28799653
  qualifier: located_in
  review:
    summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions.
    action: ACCEPT
    reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
- term:
    id: GO:0005912
    label: adherens junction
  evidence_type: IDA
  original_reference_id: PMID:28799653
  qualifier: located_in
  review:
    summary: Adherens-junction localization (IDA) reflects kindlin-2 at cell-cell adhesion sites in some epithelial contexts; secondary to its principal cell-matrix focal-adhesion localization.
    action: KEEP_AS_NON_CORE
    reason: Cell-cell junction context is secondary to the core cell-matrix focal-adhesion site.
- term:
    id: GO:0034334
    label: adherens junction maintenance
  evidence_type: IMP
  original_reference_id: PMID:28799653
  qualifier: involved_in
  review:
    summary: Kindlin-2 contributes to maintaining adherens junctions, a downstream tissue-integrity role distinct from its proximal integrin/focal-adhesion adapter activity.
    action: KEEP_AS_NON_CORE
    reason: Downstream junction-maintenance process, not the proximal integrin-adhesion function.
- term:
    id: GO:0043116
    label: negative regulation of vascular permeability
  evidence_type: IMP
  original_reference_id: PMID:28799653
  qualifier: involved_in
  review:
    summary: Reduces vascular permeability (IMP) via endothelial adhesion/junction integrity, a physiological consequence of kindlin-2 adhesion function rather than its proximal molecular role.
    action: KEEP_AS_NON_CORE
    reason: Endothelial-barrier phenotype downstream of the core adhesion role.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18528435
  qualifier: located_in
  review:
    summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions.
    action: ACCEPT
    reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: PMID:18528435
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0010718
    label: positive regulation of epithelial to mesenchymal transition
  evidence_type: IDA
  original_reference_id: PMID:24226523
  qualifier: involved_in
  review:
    summary: Promotes EMT (IDA), likely via TGF-beta/Wnt crosstalk; a pleiotropic cell-state transition downstream of kindlin-2 adhesion and signaling roles.
    action: KEEP_AS_NON_CORE
    reason: EMT promotion is downstream pleiotropic crosstalk, not the adhesion core.
- term:
    id: GO:0051897
    label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
  evidence_type: IDA
  original_reference_id: PMID:24226523
  qualifier: involved_in
  review:
    summary: Promotes PI3K/AKT signaling (IDA), a downstream survival/growth cascade activated through integrin adhesion; a secondary signaling output of kindlin-2.
    action: KEEP_AS_NON_CORE
    reason: Downstream PI3K/AKT signaling output of the adhesion core, not the proximal function.
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IDA
  original_reference_id: PMID:24226523
  qualifier: involved_in
  review:
    summary: Promotes ERK1/2 signaling (IDA) as a downstream consequence of integrin-mediated adhesion signaling; a secondary signaling output of the adhesion core.
    action: KEEP_AS_NON_CORE
    reason: Downstream MAPK output of adhesion signaling, not the proximal adapter function.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: PMID:23723426
  qualifier: located_in
  review:
    summary: Cytosolic pool (IDA/TAS) of kindlin-2 before/while it is recruited to membrane adhesion sites; consistent with a soluble cytoplasmic adapter.
    action: ACCEPT
    reason: Soluble cytosolic pool of a cytoplasmic adhesion adapter.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:23723426
  qualifier: located_in
  review:
    summary: Plasma-membrane localization (IDA) is where kindlin-2 binds integrin beta tails and inner-leaflet phosphoinositides; consistent with its membrane-proximal adapter role.
    action: ACCEPT
    reason: Plasma-membrane localization is core to integrin-tail and lipid engagement.
- term:
    id: GO:0034713
    label: type I transforming growth factor beta receptor binding
  evidence_type: IPI
  original_reference_id: PMID:23723426
  qualifier: enables
  review:
    summary: Binding the type I TGF-beta receptor (IPI) supports kindlin-2's modulation of TGF-beta/SMAD signaling; a specific partner in a pleiotropic pathway, not the adhesion core.
    action: KEEP_AS_NON_CORE
    reason: Specific TGF-beta receptor partner underlying pleiotropic signaling, peripheral to adhesion.
- term:
    id: GO:0046332
    label: SMAD binding
  evidence_type: IPI
  original_reference_id: PMID:23723426
  qualifier: enables
  review:
    summary: SMAD binding (IPI) underlies kindlin-2 participation in TGF-beta/SMAD crosstalk; a secondary signaling partner, peripheral to its integrin-adapter core.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic TGF-beta signaling partner, not part of the proximal integrin-adhesion function.
- term:
    id: GO:1900182
    label: positive regulation of protein localization to nucleus
  evidence_type: IDA
  original_reference_id: PMID:23723426
  qualifier: involved_in
  review:
    summary: Promotes nuclear localization of a partner (e.g. beta-catenin, IDA), part of kindlin-2's moonlighting transcriptional role; distinct from its cytoplasmic adhesion function.
    action: KEEP_AS_NON_CORE
    reason: Nuclear-trafficking role tied to moonlighting transcription, peripheral to adhesion.
- term:
    id: GO:0003779
    label: actin binding
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: enables
  review:
    summary: Kindlin-2 binds actin, contributing to the physical connection between integrin-based ECM adhesion sites and the actin cytoskeleton; central to its cytoskeletal-linker adapter role.
    action: ACCEPT
    reason: Direct actin binding is part of the defining integrin-to-actin linkage function.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: PMID:29496737
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:30254023
  qualifier: enables
  review:
    summary: Kindlin-2 binds protein kinase partners (e.g. ILK within the kindlin-ILK-PINCH/IPP focal-adhesion complex), a specific interaction central to assembling the integrin adhesome.
    action: ACCEPT
    reason: Specific kinase (ILK/adhesome) binding is part of the core focal-adhesion scaffolding role.
- term:
    id: GO:0022604
    label: regulation of cell morphogenesis
  evidence_type: IMP
  original_reference_id: PMID:30254023
  qualifier: involved_in
  review:
    summary: Regulates cell morphogenesis/shape (IMP) via orchestration of actin assembly at integrin adhesions; cell-shape modulation is an intrinsic part of kindlin-2's described function.
    action: ACCEPT
    reason: Cell-shape/morphogenesis modulation is an intrinsic core kindlin-2 function.
- term:
    id: GO:0045599
    label: negative regulation of fat cell differentiation
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: involved_in
  review:
    summary: Inhibits adipocyte differentiation (IMP), a cell-fate output of kindlin-2 adhesion/signaling crosstalk, downstream and tissue-specific relative to the integrin-adapter core.
    action: KEEP_AS_NON_CORE
    reason: Cell-differentiation output downstream of adhesion signaling, not the core function.
- term:
    id: GO:0045669
    label: positive regulation of osteoblast differentiation
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: involved_in
  review:
    summary: Promotes osteoblast differentiation (IMP), a skeletal cell-fate output linked to integrin/fibronectin adhesion; downstream and tissue-specific relative to the adapter core.
    action: KEEP_AS_NON_CORE
    reason: Tissue-specific differentiation output downstream of integrin adhesion.
- term:
    id: GO:0051496
    label: positive regulation of stress fiber assembly
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: involved_in
  review:
    summary: Promotes stress-fiber assembly (IMP) by coupling integrin adhesions to actin, reflecting kindlin-2's integrin-to-cytoskeleton linkage and cell-shape modulation.
    action: ACCEPT
    reason: Stress-fiber promotion follows directly from the integrin-actin linker role.
- term:
    id: GO:0051894
    label: positive regulation of focal adhesion assembly
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: involved_in
  review:
    summary: Promotes focal-adhesion assembly (IMP) as a direct consequence of kindlin-2-driven integrin activation and adhesome recruitment; a core adhesion process.
    action: ACCEPT
    reason: Promoting focal-adhesion assembly is part of the core adhesion function.
- term:
    id: GO:1902414
    label: protein localization to cell junction
  evidence_type: IMP
  original_reference_id: PMID:30254023
  qualifier: acts_upstream_of_or_within
  review:
    summary: Targets partner proteins (e.g. FBLIM1) to adhesion junctions (IMP); a specific recruitment activity supporting, but downstream of, the proximal integrin-adapter role.
    action: KEEP_AS_NON_CORE
    reason: Partner-recruitment-to-junction activity downstream of the core scaffolding function.
- term:
    id: GO:1902462
    label: positive regulation of mesenchymal stem cell proliferation
  evidence_type: IMP
  original_reference_id: PMID:29496737
  qualifier: involved_in
  review:
    summary: Promotes MSC proliferation (IMP), a cell-type-specific growth output of kindlin-2 adhesion/signaling activity, downstream of its proximal integrin-adapter role.
    action: KEEP_AS_NON_CORE
    reason: Cell-type-specific proliferation output downstream of adhesion function.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:30382829
  qualifier: located_in
  review:
    summary: Plasma-membrane localization (IDA) is where kindlin-2 binds integrin beta tails and inner-leaflet phosphoinositides; consistent with its membrane-proximal adapter role.
    action: ACCEPT
    reason: Plasma-membrane localization is core to integrin-tail and lipid engagement.
- term:
    id: GO:0007155
    label: cell adhesion
  evidence_type: IMP
  original_reference_id: PMID:30382829
  qualifier: acts_upstream_of_or_within
  review:
    summary: Kindlin-2 is required for integrin-mediated cell adhesion to the ECM (IGI/IMP); a core process directly arising from its integrin co-activation and focal-adhesion assembly activities.
    action: ACCEPT
    reason: Cell adhesion is a core process directly mediated by kindlin-2.
- term:
    id: GO:0030054
    label: cell junction
  evidence_type: IDA
  original_reference_id: PMID:30382829
  qualifier: located_in
  review:
    summary: Generic cell-junction localization (IDA); kindlin-2's specific and defining junction is the cell-matrix focal adhesion, captured by more precise terms.
    action: KEEP_AS_NON_CORE
    reason: Generic junction term subsumed by the specific focal-adhesion localization.
- term:
    id: GO:0030335
    label: positive regulation of cell migration
  evidence_type: IMP
  original_reference_id: PMID:30382829
  qualifier: involved_in
  review:
    summary: Promotes cell migration (IMP), a downstream behavior enabled by kindlin-2-driven focal-adhesion dynamics and integrin activation rather than a defining molecular function.
    action: KEEP_AS_NON_CORE
    reason: Migration is a downstream cellular behavior of the integrin-adhesion core.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: PMID:29162887
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: HDA
  original_reference_id: PMID:21423176
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-430341
  qualifier: located_in
  review:
    summary: Cytosolic pool (IDA/TAS) of kindlin-2 before/while it is recruited to membrane adhesion sites; consistent with a soluble cytoplasmic adapter.
    action: ACCEPT
    reason: Soluble cytosolic pool of a cytoplasmic adhesion adapter.
- term:
    id: GO:0005547
    label: phosphatidylinositol-3,4,5-trisphosphate binding
  evidence_type: IDA
  original_reference_id: PMID:21325030
  qualifier: enables
  review:
    summary: The PH domain binds PIP3 preferentially (NMR structure, PMID:22030399); K383/K385 mutations reduce lipid binding and integrin activation, making this lipid-binding activity core to membrane targeting.
    action: ACCEPT
    reason: PH-domain PIP3 binding is mechanistically required for membrane-proximal integrin activation.
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:22699938
  qualifier: located_in
  review:
    summary: Nuclear localization underlies kindlin-2's moonlighting role in Wnt/beta-catenin transcriptional regulation; distinct from its principal cytoplasmic focal-adhesion function.
    action: KEEP_AS_NON_CORE
    reason: Secondary nuclear/transcriptional role, separate from the core integrin-adhesion function.
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:22699938
  qualifier: located_in
  review:
    summary: Kindlin-2 is a cytoplasmic protein (IDA); consistent with its role as a cytosolic adapter recruited to membrane-proximal integrin tails and focal adhesions.
    action: ACCEPT
    reason: Bulk cytoplasmic localization matches a cytoplasmic adhesion adapter.
- term:
    id: GO:0005925
    label: focal adhesion
  evidence_type: IDA
  original_reference_id: PMID:21325030
  qualifier: located_in
  review:
    summary: Focal adhesion is the defining subcellular site of kindlin-2, where it co-localizes with actin stress fibers at cell-ECM adhesions and recruits partners such as FBLIM1.
    action: ACCEPT
    reason: Focal adhesion is the central, defining localization of kindlin-2.
- term:
    id: GO:0007160
    label: cell-matrix adhesion
  evidence_type: IMP
  original_reference_id: PMID:21325030
  qualifier: involved_in
  review:
    summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core.
    action: ACCEPT
    reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
- term:
    id: GO:0007179
    label: transforming growth factor beta receptor signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:21325030
  qualifier: involved_in
  review:
    summary: Participates in TGF-beta receptor signaling (IMP) via receptor/SMAD interactions; a pleiotropic signaling role distinct from the integrin-adhesion core.
    action: KEEP_AS_NON_CORE
    reason: Pleiotropic TGF-beta signaling role, separate from the core adhesion function.
- term:
    id: GO:0007229
    label: integrin-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:21325030
  qualifier: involved_in
  review:
    summary: Initiates/propagates integrin-mediated (inside-out and outside-in) signaling through integrin-tail engagement and adhesome assembly; a core signaling process for kindlin-2.
    action: ACCEPT
    reason: Integrin signaling is a core pathway directly engaged by kindlin-2.
- term:
    id: GO:0016055
    label: Wnt signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:22699938
  qualifier: involved_in
  review:
    summary: Kindlin-2 stabilizes active CTNNB1 and forms a complex with CTNNB1/TCF7L2 to enhance Wnt-driven transcription (PMID:22699938); a moonlighting nuclear role distinct from focal-adhesion adhesion.
    action: KEEP_AS_NON_CORE
    reason: Nuclear Wnt/beta-catenin crosstalk is a pleiotropic moonlighting role, not the core adhesion function.
- term:
    id: GO:0005547
    label: phosphatidylinositol-3,4,5-trisphosphate binding
  evidence_type: IDA
  original_reference_id: PMID:22030399
  qualifier: enables
  review:
    summary: The PH domain binds PIP3 preferentially (NMR structure, PMID:22030399); K383/K385 mutations reduce lipid binding and integrin activation, making this lipid-binding activity core to membrane targeting.
    action: ACCEPT
    reason: PH-domain PIP3 binding is mechanistically required for membrane-proximal integrin activation.
- term:
    id: GO:0007160
    label: cell-matrix adhesion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Enhances integrin-mediated cell adhesion onto the extracellular matrix, requiring both integrin and phospholipid binding; the precise adhesion process at kindlin-2's core.
    action: ACCEPT
    reason: Cell-matrix adhesion is the defining biological process of kindlin-2.
- term:
    id: GO:0033622
    label: integrin activation
  evidence_type: IMP
  original_reference_id: PMID:22030399
  qualifier: involved_in
  review:
    summary: 'Co-activates integrins with talin: binding the membrane-distal beta-tail NPxY motif, kindlin-2 enhances affinity maturation; QW614-615AA abolishes ITGB3 binding and activation enhancement.'
    action: ACCEPT
    reason: Integrin (co-)activation is the central molecular process defining kindlin-2.
- term:
    id: GO:0034446
    label: substrate adhesion-dependent cell spreading
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Mediates substrate adhesion-dependent cell spreading (ISS); kindlin-2 enhancement of ECM adhesion and lamellipodial integrin engagement drives cell spreading.
    action: ACCEPT
    reason: Substrate-dependent spreading is a core process driven by kindlin-2 adhesion activity.
- term:
    id: GO:0048041
    label: focal adhesion assembly
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Kindlin-2 is required for focal-adhesion assembly; its integrin co-activation nucleates the adhesion complex, a core process supported by IMP/ISS evidence.
    action: ACCEPT
    reason: Focal-adhesion assembly is a core process requiring kindlin-2.
- term:
    id: GO:0072657
    label: protein localization to membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Recruits/retains partners at the plasma membrane (ISS) as part of assembling the membrane-proximal integrin adhesion complex; integral to kindlin-2's scaffolding role.
    action: ACCEPT
    reason: Membrane recruitment of adhesome partners is part of the core scaffolding function.
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:18528435
  title: Colocalization of kindlin-1, kindlin-2, and migfilin at keratinocyte focal adhesion and relevance to the pathophysiology of Kindler syndrome.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full text supports kindlin-2 focal-adhesion localization and relationship to kindlin/migfilin cell-matrix adhesion complexes.
- id: PMID:21325030
  title: Kindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract directly supports integrin binding, phosphoinositide binding, integrin activation, podocyte matrix adhesion, fibronectin deposition, and focal-adhesion localization, but full text is unavailable in cache.
- id: PMID:21356350
  title: Kindlin-1 and -2 have overlapping functions in epithelial cells implications for phenotype modification.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text supports kindlin-2 roles in epithelial focal adhesions, actin organization, beta1 integrin activation, adhesion, survival, and migration.
- id: PMID:21423176
  title: Analysis of the myosin-II-responsive focal adhesion proteome reveals a role for β-Pix in negative regulation of focal adhesion maturation.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cached full text is a focal-adhesion proteome study; supports focal-adhesion detection/context but is not direct FERMT2 mechanistic evidence.
- id: PMID:22030399
  title: Structural basis of phosphoinositide binding to kindlin-2 protein pleckstrin homology domain in regulating integrin activation.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Abstract directly supports kindlin-2 PH-domain PIP3 binding and the role of phosphoinositide binding in talin-cooperative integrin activation.
- id: PMID:22699938
  title: Kindlin 2 forms a transcriptional complex with β-catenin and TCF4 to enhance Wnt signalling.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports beta-catenin/TCF4 complex formation and Wnt signaling enhancement; full text unavailable.
- id: PMID:23723426
  title: Kindlin-2 mediates activation of TGF-β/Smad signaling and renal fibrosis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports TGF-beta type I receptor and Smad3 interaction and renal fibrosis signaling; full text unavailable.
- id: PMID:24226523
  title: Kindlin-2 regulates renal tubular cell plasticity by activation of Ras and its downstream signaling.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract supports Ras/ERK/AKT activation and renal tubular EMT context; full text unavailable.
- id: PMID:25160619
  title: Molecular basis of kindlin-2 binding to integrin-linked kinase pseudokinase for regulating cell adhesion.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached abstract maps high-affinity kindlin-2 binding to ILK and shows its requirement for focal-adhesion localization and spreading; full text unavailable.
- id: PMID:28799653
  title: Kindlin-2 interacts with endothelial adherens junctions to support vascular barrier integrity.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full text supports endothelial adherens-junction localization, beta/gamma-catenin and actin interaction, and vascular-barrier maintenance.
- id: PMID:29162887
  title: The WD40-domain containing protein CORO2B is specifically enriched in glomerular podocytes and regulates the ventral actin cytoskeleton.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Cached full text is primarily about CORO2B/podocyte focal adhesions; FERMT2 support is focal-adhesion/proteomic context rather than direct function.
- id: PMID:29496737
  title: Kindlin-2 regulates mesenchymal stem cell differentiation through control of YAP1/TAZ.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full text supports RhoA/MLCK/stress-fiber/focal-adhesion assembly and MSC fate phenotypes.
- id: PMID:30254023
  title: Kindlin-2 interacts with a highly conserved surface of ILK to regulate focal adhesion localization and cell spreading.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached full text directly supports the ILK-kindlin-2 interaction, focal-adhesion localization, and cell-spreading output.
- id: PMID:30382829
  title: Fermitin family homolog-2 (FERMT2) is highly expressed in human placental villi and modulates trophoblast invasion.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached full text supports placental FERMT2 expression and trophoblast adhesion/migration/invasion context.
- id: Reactome:R-HSA-430341
  title: Mig-2 recruits Migfilin to the cell-ECM adhesions
  findings: []
core_functions:
- description: Integrin-binding adaptor/co-activator function at focal adhesions and cytoplasmic membrane adhesion sites, cooperating with talin and phosphoinositide-rich membranes to promote integrin activation, cell-matrix adhesion, focal adhesion assembly, and substrate-dependent spreading.
  supported_by:
  - reference_id: PMID:21325030
    supporting_text: Kindlin-2 is a FERM and PH domain-containing integrin-binding protein
  - reference_id: PMID:21325030
    supporting_text: depletion of kindlin-2 reduced integrin activation, matrix adhesion and fibronectin matrix deposition
  - reference_id: PMID:22030399
    supporting_text: this ability is significantly impaired for a phosphoinositide binding-defective kindlin-2 mutant
  molecular_function:
    id: GO:0005178
    label: integrin binding
  directly_involved_in:
  - id: GO:0033622
    label: integrin activation
  - id: GO:0007229
    label: integrin-mediated signaling pathway
  - id: GO:0007160
    label: cell-matrix adhesion
  - id: GO:0048041
    label: focal adhesion assembly
  - id: GO:0034446
    label: substrate adhesion-dependent cell spreading
  locations:
  - id: GO:0005925
    label: focal adhesion
  - id: GO:0009898
    label: cytoplasmic side of plasma membrane
  - id: GO:0031258
    label: lamellipodium membrane
- description: PH-domain phosphatidylinositol-3,4,5-trisphosphate binding that supports membrane engagement and talin-cooperative integrin activation.
  supported_by:
  - reference_id: PMID:21325030
    supporting_text: kindlin-2 interacts with multiple phosphoinositides, preferentially with phosphatidylinositol 3,4,5-trisphosphate
  - reference_id: PMID:22030399
    supporting_text: PIP3 site-specifically binds to kindlin-2 PH
  - reference_id: PMID:22030399
    supporting_text: the PH domain mediates membrane engagement of kindlin-2 to promote its binding to integrin
  molecular_function:
    id: GO:0005547
    label: phosphatidylinositol-3,4,5-trisphosphate binding
  directly_involved_in:
  - id: GO:0033622
    label: integrin activation
  - id: GO:0072657
    label: protein localization to membrane
  locations:
  - id: GO:0009898
    label: cytoplasmic side of plasma membrane
  - id: GO:0005925
    label: focal adhesion
- description: Actin- and ILK-linked focal-adhesion scaffold function that couples integrin adhesion complexes to cytoskeletal organization, RhoA signaling, stress-fiber assembly, focal-adhesion localization, and cell morphology.
  supported_by:
  - reference_id: PMID:30254023
    supporting_text: the interaction between ILK and kindlin-2 is critical for cell spreading and focal adhesion localization
  - reference_id: PMID:29496737
    supporting_text: Kindlin-2 is an important integrin- and actin-binding protein
  - reference_id: PMID:29496737
    supporting_text: Loss of kindlin-2 inhibits RhoA activation and reduces myosin light-chain phosphorylation, stress fiber formation, and focal adhesion assembly
  molecular_function:
    id: GO:0003779
    label: actin binding
  directly_involved_in:
  - id: GO:0035025
    label: positive regulation of Rho protein signal transduction
  - id: GO:0051496
    label: positive regulation of stress fiber assembly
  - id: GO:0051894
    label: positive regulation of focal adhesion assembly
  - id: GO:0022604
    label: regulation of cell morphogenesis
  locations:
  - id: GO:0005925
    label: focal adhesion
  - id: GO:0005856
    label: cytoskeleton
  - id: GO:0001725
    label: stress fiber
  - id: GO:0005938
    label: cell cortex
proposed_new_terms: []
suggested_questions:
- question: Which FERMT2 pathway outputs should be treated as general kindlin-2 biology versus cell-type-specific consequences of integrin/focal-adhesion scaffolding?
- question: Does Alzheimer-associated FERMT2 biology act through brain vascular barrier, microglial adhesion/migration, synaptic extracellular-matrix responses, or a different cell type?
- question: Can partner-specific annotations replace remaining generic or context-dependent interaction terms after full-text review of the source papers?
suggested_experiments:
- hypothesis: FERMT2 Alzheimer relevance depends on integrin/focal-adhesion regulation in vascular or glial cell adhesion states.
  description: Perturb FERMT2 in human iPSC-derived endothelial cells, pericytes, astrocytes, and microglia, then quantify integrin activation, focal-adhesion dynamics, barrier integrity, migration, and extracellular-matrix responses under amyloid or inflammatory stress.
  experiment_type: cell-type-specific adhesion and barrier assay
- hypothesis: FERMT2 phosphoinositide binding controls integrin activation by recruiting kindlin-2 to PIP3-rich adhesion membranes.
  description: Compare wild-type FERMT2 with PH-domain phosphoinositide-binding mutants in endogenous rescue assays measuring PIP3-dependent membrane recruitment, talin cooperation, integrin activation, focal-adhesion assembly, and cell spreading.
  experiment_type: structure-function rescue assay

Gene Description

Existing Annotations Review

Core Functions

Integrin-binding adaptor/co-activator function at focal adhesions and cytoplasmic membrane adhesion sites, cooperating with talin and phosphoinositide-rich membranes to promote integrin activation, cell-matrix adhesion, focal adhesion assembly, and substrate-dependent spreading.

PH-domain phosphatidylinositol-3,4,5-trisphosphate binding that supports membrane engagement and talin-cooperative integrin activation.

Actin- and ILK-linked focal-adhesion scaffold function that couples integrin adhesion complexes to cytoskeletal organization, RhoA signaling, stress-fiber assembly, focal-adhesion localization, and cell morphology.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

FERMT2 notes

2026-06-20 second-pass audit

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