id: MODULE:chemokine_signaling title: Chemokine-mediated signaling pathway module description: >- Secreted chemokines (exemplified by the ELR-positive CXC chemokine CXCL8/IL-8) bind glycosaminoglycans in the extracellular region and engage seven-transmembrane Gi-coupled chemokine receptors (such as CXCR1/CXCR2 for CXCL8 and CCR5 for CC chemokines) at the leukocyte plasma membrane. Agonist binding initiates the chemokine-mediated signaling pathway (GO:0070098) and the specific interleukin-8-mediated signaling pathway (GO:0038112), promoting heterotrimeric Gi nucleotide exchange and Gbetagamma/Galpha_i signaling through PI3Kgamma (PIK3CG), phospholipase C beta calcium mobilization, and RhoA-dependent actomyosin remodeling to direct leukocyte chemotaxis (GO:0060326) and neutrophil chemotaxis (GO:0030593). status: DRAFT evidence: - source_id: file:modules/chemokine_signaling-deep-research-falcon.md title: Chemokine-mediated signaling pathway Falcon module review statement: >- Falcon/Edison module review generated 2026-06-28 is linked as supporting evidence for module boundaries, core mechanism, variation, constraints, and failure modes; open questions in that report require manual review before promotion to curated knowledge gaps. - source_id: GO:0070098 title: chemokine-mediated signaling pathway statement: >- The module is grounded in the GO biological process term for chemokine-mediated signaling pathway (GO:0070098) and its ligand-specific child term interleukin-8-mediated signaling pathway (GO:0038112). - source_id: GO:0038112 title: interleukin-8-mediated signaling pathway statement: >- Specific child pathway initiated by CXCL8 (interleukin-8) binding to CXCR1 and CXCR2 on neutrophils and other target cells. - source_id: PMID:1840701 title: Structure and functional expression of a human interleukin-8 receptor. supporting_text: >- Mammalian cells transfected with the IL-8 receptor cDNA clone bind IL-8 with high affinity and respond specifically to IL-8 by transiently mobilizing calcium. statement: >- Establishes high-affinity CXCL8 binding to cloned human CXCR1 and downstream calcium mobilization. - source_id: PMID:32610344 title: Structural basis of CXC chemokine receptor 2 activation and signalling. supporting_text: >- Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. statement: >- Resolves the active ternary signaling complex of CXCL8, CXCR2, and heterotrimeric Gi. - source_id: PMID:37433790 title: Structural basis of CXC chemokine receptor 1 ligand binding and activation. supporting_text: >- Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. statement: >- Resolves the cryo-EM structure of the active CXCL8-CXCR1-Gi signaling complex. - source_id: PANTHER:PTN002564680 title: PAINT node PTN002564680 for ELR-positive CXC chemokines (CXCL8) statement: >- Local PAINT IBD node in PTHR12015 with propagated terms C:GO:0005576, F:GO:0008009, F:GO:0045236, P:GO:0006954, P:GO:0030593, P:GO:0061844, P:GO:0071222; PAINT date 20260828. - source_id: PANTHER:PTN001628461 title: PAINT node PTN001628461 for chemokine receptors (CXCR2, CCR5) statement: >- Local PAINT IBD node in PTHR10489 with propagated terms C:GO:0009897, F:GO:0016493, F:GO:0019957, P:GO:0006955, P:GO:0007204, P:GO:0019722, P:GO:0060326; PAINT date 20260828. - source_id: PANTHER:PTN002573743 title: PAINT node PTN002573743 for CXCR2 neutrophil chemotaxis statement: >- Local PAINT IBD node in PTHR10489 with propagated terms P:GO:0030593; PAINT date 20200312. - source_id: PANTHER:PTN000026392 title: PAINT node PTN000026392 for G protein alpha subunits (GNAI2) statement: >- Local PAINT IBD node in PTHR10218 with propagated terms C:GO:0005737, C:GO:0005834, F:GO:0003925, P:GO:0007188; PAINT date 20260828. - source_id: PANTHER:PTN000005673 title: PAINT node PTN000005673 for PIK3CG statement: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005737, C:GO:0016020, F:GO:0052742, P:GO:0046854; PAINT date 20260528. - source_id: PANTHER:PTN000005674 title: PAINT node PTN000005674 for PIK3CG statement: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005886, F:GO:0016303, F:GO:0035005, P:GO:0043491; PAINT date 20240205. - source_id: PANTHER:PTN000632671 title: PAINT node PTN000632671 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005886, F:GO:0003924, F:GO:0005525, P:GO:0007015, P:GO:0007165; PAINT date 20260529. - source_id: PANTHER:PTN000799655 title: PAINT node PTN000799655 for PIK3CG statement: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005942; PAINT date 20240516. - source_id: PANTHER:PTN000799659 title: PAINT node PTN000799659 for PIK3CG statement: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005943, C:GO:0005944, F:GO:0046934; PAINT date 20240918. - source_id: PANTHER:PTN001178055 title: PAINT node PTN001178055 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0016477; PAINT date 20250903. - source_id: PANTHER:PTN002784793 title: PAINT node PTN002784793 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0007266, P:GO:0043149; PAINT date 20231109. - source_id: PANTHER:PTN008393484 title: PAINT node PTN008393484 for RHOA statement: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005829, P:GO:0032956; PAINT date 20260529. notes: >- Curated signaling-pathway module upgraded from GENE_PRODUCT exemplars to PANTHER FAMILY/subfamily selectors with explicit molecular functions, biological processes, cellular locations, and PAINT/experimental evidence across all participants. The CXCL8-CXCR2 arm models the specific interleukin-8-mediated signaling pathway (GO:0038112) and neutrophil chemotaxis (GO:0030593) within the general chemokine-mediated signaling pathway (GO:0070098). Retained Falcon deep-research citations in references are machine-generated and have not been manually adjudicated against primary literature. module: id: chemokine_signaling label: Chemokine-mediated signaling pathway module_type: SIGNALING_PATHWAY concepts: - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway description: >- Chemokines activate seven-transmembrane chemokine receptors and heterotrimeric G proteins, coordinating PI3K, calcium, and Rho-family pathways that direct leukocyte migration and positioning. - preferred_term: interleukin-8-mediated signaling pathway term: id: GO:0038112 label: interleukin-8-mediated signaling pathway description: >- The series of molecular signals initiated by interleukin-8 (CXCL8) binding to its receptors CXCR1 or CXCR2 on the surface of a target cell to drive neutrophil chemotaxis and activation. context: taxa: - preferred_term: metazoa term: id: NCBITaxon:33208 label: Metazoa cellular_components: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol - preferred_term: nucleus term: id: GO:0005634 label: nucleus parts: - order: 1 role: chemokine-receptor engagement node: id: chemokine_receptor_engagement label: Chemokine receptor engagement module_type: REGULATORY_STEP description: >- Secreted chemokine ligands (exemplified by CXCL8/IL-8) engage seven-transmembrane chemokine receptors (CXCR1/CXCR2 for CXC chemokines; CCR5 for CC chemokines) via a two-site binding mechanism. annotons: - id: cxcl8_cxcl8_chemokine_ligand label: CXCL8 chemokine ligand participant: selector_type: FAMILY family: preferred_term: Interleukin-8 (CXCL8) chemokine ligand subfamily term: id: PANTHER:PTHR12015:SF200 label: INTERLEUKIN-8 representative_members: - preferred_term: CXCL8 term: id: UniProtKB:P10145 label: 'Interleukin-8 (IL-8) (C-X-C motif chemokine 8) (Chemokine (C-X-C motif) ligand 8) (Emoctakin) (Granulocyte chemotactic protein 1) (GCP-1) (Monocyte-derived neutrophil chemotactic factor) (MDNCF) (Monocyte-derived neutrophil-activating peptide) (MONAP) (Neutrophil-activating protein 1) (NAP-1) (Protein 3-10C) (T-cell chemotactic factor) [Cleaved into: MDNCF-a (GCP/IL-8 protein IV) (IL8/NAP1 form I); Interleukin-8 ((Ala-IL-8)77) (GCP/IL-8 protein II) (IL-8(1-77)) (IL8/NAP1 form II) (MDNCF-b); IL-8(5-77); IL-8(6-77) ((Ser-IL-8)72) (GCP/IL-8 protein I) (IL8/NAP1 form III) (Lymphocyte-derived neutrophil-activating factor) (LYNAP) (MDNCF-c) (Neutrophil-activating factor) (NAF); IL-8(7-77) (GCP/IL-8 protein V) (IL8/NAP1 form IV); IL-8(8-77) (GCP/IL-8 protein VI) (IL8/NAP1 form V); IL-8(9-77) (GCP/IL-8 protein III) (IL8/NAP1 form VI)]' ancestral_nodes: - preferred_term: PAINT node PTN002564680 for ELR-positive CXC chemokines term: id: PANTHER:PTN002564680 label: PTN002564680 description: >- Local PAINT IBD node in PTHR12015 with propagated terms C:GO:0005576, F:GO:0008009, F:GO:0045236, P:GO:0006954, P:GO:0030593, P:GO:0061844, P:GO:0071222; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002564680 in PTHR12015. evidence: - source_id: file:interpro/panther/PTHR12015/PTHR12015-review.yaml title: PTHR12015 PANTHER family review statement: >- PTHR12015 review scopes GO:0038112 (interleukin-8-mediated signaling pathway) and GO:0005153 (interleukin-8 receptor binding) to PANTHER:PTHR12015:SF200 (INTERLEUKIN-8) within the PTN002564680 ELR-positive CXC chemokine clade. function: preferred_term: chemokine activity term: id: GO:0008009 label: chemokine activity processes: - preferred_term: interleukin-8-mediated signaling pathway term: id: GO:0038112 label: interleukin-8-mediated signaling pathway - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway - preferred_term: neutrophil chemotaxis term: id: GO:0030593 label: neutrophil chemotaxis locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted ELR-positive CXC chemokine ligand that binds glycosaminoglycans and activates CXCR1/CXCR2 to initiate the interleukin-8-mediated signaling pathway and neutrophil chemotaxis. evidence: - source_id: PMID:8399143 title: 'Human and bovine granulocyte chemotactic protein-2: complete amino acid sequence and functional characterization as chemokines.' supporting_text: >- Both chemokines can also activate postreceptor mechanisms leading to release of gelatinase B by granulocytes. statement: >- Demonstrates CXCL8 (IL-8) chemokine activity, neutrophil chemotaxis, and post-receptor signaling. - source_id: PMID:32610344 title: Structural basis of CXC chemokine receptor 2 activation and signalling. supporting_text: >- Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. statement: >- Resolves CXCL8 bound to CXCR2 in the active Gi-coupled signaling complex. - id: cxcr2_cxcr2_chemokine_receptor label: CXCR2 chemokine receptor participant: selector_type: FAMILY family: preferred_term: C-X-C chemokine receptor type 2 subfamily term: id: PANTHER:PTHR10489:SF689 label: C-X-C CHEMOKINE RECEPTOR TYPE 2 representative_members: - preferred_term: CXCR2 term: id: UniProtKB:P25025 label: C-X-C chemokine receptor type 2 (CXC-R2) (CXCR-2) (CDw128b) (GRO/MGSA receptor) (High affinity interleukin-8 receptor B) (IL-8R B) (IL-8 receptor type 2) (CD antigen CD182) ancestral_nodes: - preferred_term: PAINT node PTN001628461 for chemokine receptors term: id: PANTHER:PTN001628461 label: PTN001628461 description: >- Local PAINT IBD node in PTHR10489 with propagated terms C:GO:0009897, F:GO:0016493, F:GO:0019957, P:GO:0006955, P:GO:0007204, P:GO:0019722, P:GO:0060326; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001628461 in PTHR10489. - preferred_term: PAINT node PTN002573743 for CXCR1/CXCR2 term: id: PANTHER:PTN002573743 label: PTN002573743 description: >- Local PAINT IBD node in PTHR10489 with propagated terms P:GO:0030593; PAINT date 20200312. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002573743 in PTHR10489. evidence: - source_id: file:interpro/panther/PTHR10489/PTHR10489-review.yaml title: PTHR10489 PANTHER family review statement: >- PTHR10489 review documents clade-specific CXCR1/CXCR2 neutrophil chemotaxis (PTN002573743) within the chemokine receptor clade (PTN001628461). function: preferred_term: C-X-C chemokine receptor activity term: id: GO:0016494 label: C-X-C chemokine receptor activity processes: - preferred_term: interleukin-8-mediated signaling pathway term: id: GO:0038112 label: interleukin-8-mediated signaling pathway - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway - preferred_term: neutrophil chemotaxis term: id: GO:0030593 label: neutrophil chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- High-affinity seven-transmembrane CXC chemokine receptor on neutrophils and endothelial cells that binds CXCL8 and other ELR-positive CXC chemokines to activate heterotrimeric Gi signaling. evidence: - source_id: PMID:32610344 title: Structural basis of CXC chemokine receptor 2 activation and signalling. supporting_text: >- Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. statement: >- Demonstrates CXCL8-induced activation of human CXCR2 and coupling to Gi. - id: ccr5_ccr5_chemokine_receptor label: CCR5 chemokine receptor participant: selector_type: FAMILY family: preferred_term: C-C chemokine receptor type 5 subfamily term: id: PANTHER:PTHR10489:SF686 label: C-C CHEMOKINE RECEPTOR TYPE 5 representative_members: - preferred_term: CCR5 term: id: UniProtKB:P51681 label: C-C chemokine receptor type 5 (C-C CKR-5) (CC-CKR-5) (CCR-5) (CCR5) (CHEMR13) (HIV-1 fusion coreceptor) (CD antigen CD195) ancestral_nodes: - preferred_term: PAINT node PTN001628461 for chemokine receptors term: id: PANTHER:PTN001628461 label: PTN001628461 description: >- Local PAINT IBD node in PTHR10489 with propagated terms C:GO:0009897, F:GO:0016493, F:GO:0019957, P:GO:0006955, P:GO:0007204, P:GO:0019722, P:GO:0060326; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001628461 in PTHR10489. evidence: - source_id: file:interpro/panther/PTHR10489/PTHR10489-review.yaml title: PTHR10489 PANTHER family review statement: >- PTHR10489 review documents CC-chemokine receptor clade propagation at PTN001628461 (GO:0016493 C-C chemokine receptor activity and GO:0060326 cell chemotaxis). function: preferred_term: C-C chemokine receptor activity term: id: GO:0016493 label: C-C chemokine receptor activity processes: - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway - preferred_term: cell chemotaxis term: id: GO:0060326 label: cell chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Seven-transmembrane CC-motif chemokine receptor that transduces CCL3, CCL4, and CCL5 signals via heterotrimeric Gi proteins to direct monocyte and T-cell chemotaxis. evidence: - source_id: PANTHER:PTN001628461 title: PAINT node PTN001628461 for chemokine receptors statement: >- Supports CCR5 participation in GO:0016493 (C-C chemokine receptor activity) and GO:0060326 (cell chemotaxis). - order: 2 role: heterotrimeric g protein coupling node: id: gi_protein_coupling label: Gi protein coupling module_type: REGULATORY_STEP description: >- Agonist-activated chemokine receptors act as guanine nucleotide exchange factors (GEFs) for pertussis toxin-sensitive Gi-family heterotrimeric G proteins, releasing Galpha_i-GTP and Gbetagamma dimers at the inner leaflet of the plasma membrane. annotons: - id: gnai2_gnai2_alpha_subunit label: GNAI2 alpha subunit participant: selector_type: FAMILY family: preferred_term: Guanine nucleotide-binding protein G(i) subunit alpha-2 subfamily term: id: PANTHER:PTHR10218:SF73 label: GUANINE NUCLEOTIDE-BINDING PROTEIN G(I) SUBUNIT ALPHA-2 representative_members: - preferred_term: GNAI2 term: id: UniProtKB:P04899 label: Guanine nucleotide-binding protein G(i) subunit alpha-2 (EC 3.6.5.-) (Adenylate cyclase-inhibiting G alpha protein) ancestral_nodes: - preferred_term: PAINT node PTN000026392 for G protein alpha subunits term: id: PANTHER:PTN000026392 label: PTN000026392 description: >- Local PAINT IBD node in PTHR10218 with propagated terms C:GO:0005737, C:GO:0005834, F:GO:0003925, P:GO:0007188; PAINT date 20260828. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000026392 in PTHR10218. evidence: - source_id: PANTHER:PTN000026392 title: PAINT node PTN000026392 for GNAI2 statement: >- Supports heterotrimeric G protein activity (GO:0003925) and G protein-coupled receptor signaling (GO:0007186) in PTHR10218. function: preferred_term: G protein activity term: id: GO:0003925 label: G protein activity processes: - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway - preferred_term: interleukin-8-mediated signaling pathway term: id: GO:0038112 label: interleukin-8-mediated signaling pathway locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane role_description: >- Inhibitory heterotrimeric G protein alpha subunit (Galpha_i2) coupled to CXCR1, CXCR2, and CCR5 that undergoes GDP-to-GTP exchange upon chemokine binding, releasing Gbetagamma to activate PI3Kgamma and PLCbeta2/3. evidence: - source_id: PMID:32610344 title: Structural basis of CXC chemokine receptor 2 activation and signalling. supporting_text: >- Here we present the cryo-electron microscopy structures of interleukin-8 (IL-8, also known as CXCL8)-activated human CXC chemokine receptor 2 (CXCR2) in complex with Gi protein, along with a crystal structure of CXCR2 bound to a designed allosteric antagonist. statement: >- Resolves direct coupling of CXCL8-bound CXCR2 to heterotrimeric Gi. - source_id: PMID:37433790 title: Structural basis of CXC chemokine receptor 1 ligand binding and activation. supporting_text: >- Here, we solve the structure of CXCR1 complexed with CXCL8 and cognate G-proteins using cryo-EM, showing the detailed interactions between the receptor, the chemokine and Gαi protein. statement: >- Resolves direct coupling of CXCL8-bound CXCR1 to Galpha_i. - order: 3 role: chemotaxis effector output node: id: chemotaxis_effector_output label: Chemotaxis effector output module_type: REGULATORY_STEP description: >- PI3Kgamma and Rho-family GTPase branches downstream of Gi/Gbetagamma coordinate phosphoinositide polarization, actin remodeling, and directional leukocyte migration. annotons: - id: pik3cg_pi3k_gamma_catalytic_branch label: PI3K gamma catalytic branch participant: selector_type: FAMILY family: preferred_term: PI3K gamma catalytic branch family/ortholog group term: id: PANTHER:PTHR10048 label: PHOSPHATIDYLINOSITOL KINASE representative_members: - preferred_term: PIK3CG term: id: UniProtKB:P48736 label: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform (PI3-kinase subunit gamma) (PI3K-gamma) (PI3Kgamma) (PtdIns-3-kinase subunit gamma) (EC 2.7.1.137) (EC 2.7.1.153) (EC 2.7.1.154) (Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit gamma) (PtdIns-3-kinase subunit p110-gamma) (p110gamma) (Phosphoinositide-3-kinase catalytic gamma polypeptide) (Serine/threonine protein kinase PIK3CG) (EC 2.7.11.1) (p120-PI3K) ancestral_nodes: - preferred_term: PAINT node PTN000005673 for PIK3CG term: id: PANTHER:PTN000005673 label: PTN000005673 description: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005737, C:GO:0016020, F:GO:0052742, P:GO:0046854; PAINT date 20260528. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000005673 in PTHR10048. - preferred_term: PAINT node PTN000005674 for PIK3CG term: id: PANTHER:PTN000005674 label: PTN000005674 description: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005886, F:GO:0016303, F:GO:0035005, P:GO:0043491; PAINT date 20240205. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000005674 in PTHR10048. - preferred_term: PAINT node PTN000799655 for PIK3CG term: id: PANTHER:PTN000799655 label: PTN000799655 description: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005942; PAINT date 20240516. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000799655 in PTHR10048. - preferred_term: PAINT node PTN000799659 for PIK3CG term: id: PANTHER:PTN000799659 label: PTN000799659 description: Local PAINT IBD node in PTHR10048 with propagated terms C:GO:0005943, C:GO:0005944, F:GO:0046934; PAINT date 20240918. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000799659 in PTHR10048. evidence: - source_id: file:interpro/panther/PTHR10048/PTHR10048-deep-research-falcon.md title: PTHR10048 Falcon family review statement: >- Falcon family-level GO review: The absence of InterPro2GO mappings for PTHR10048 is correct and sound given the family's biochemical and biological diversity (burke2018structuralbasisfor pages 5-6, eliasvillalobos2019newinsightsinto pages 12-17, tafur2020structuralinsightsinto pages 15-18) Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. function: preferred_term: 1-phosphatidylinositol-3-kinase activity term: id: GO:0016303 label: 1-phosphatidylinositol-3-kinase activity processes: - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway - preferred_term: cell chemotaxis term: id: GO:0060326 label: cell chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Class IB phosphoinositide 3-kinase catalytic subunit (p110gamma) recruited by Gi-derived Gbetagamma dimers to generate PtdIns(3,4,5)P3 at the leading edge of chemotaxing leukocytes. evidence: - source_id: PANTHER:PTN000005674 title: PAINT node PTN000005674 for PIK3CG statement: >- Supports 1-phosphatidylinositol-3-kinase activity (GO:0016303) at the plasma membrane (GO:0005886). - id: rhoa_rhoa_cytoskeletal_switch label: RhoA cytoskeletal switch participant: selector_type: FAMILY family: preferred_term: RhoA cytoskeletal switch family/ortholog group term: id: PANTHER:PTHR24072 label: RHO FAMILY GTPASE representative_members: - preferred_term: RHOA term: id: UniProtKB:P61586 label: Transforming protein RhoA (EC 3.6.5.2) (Rho cDNA clone 12) (h12) ancestral_nodes: - preferred_term: PAINT node PTN000632671 for RHOA term: id: PANTHER:PTN000632671 label: PTN000632671 description: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005886, F:GO:0003924, F:GO:0005525, P:GO:0007015, P:GO:0007165; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN000632671 in PTHR24072. - preferred_term: PAINT node PTN001178055 for RHOA term: id: PANTHER:PTN001178055 label: PTN001178055 description: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0016477; PAINT date 20250903. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN001178055 in PTHR24072. - preferred_term: PAINT node PTN002784793 for RHOA term: id: PANTHER:PTN002784793 label: PTN002784793 description: Local PAINT IBD node in PTHR24072 with propagated terms P:GO:0007266, P:GO:0043149; PAINT date 20231109. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN002784793 in PTHR24072. - preferred_term: PAINT node PTN008393484 for RHOA term: id: PANTHER:PTN008393484 label: PTN008393484 description: Local PAINT IBD node in PTHR24072 with propagated terms C:GO:0005829, P:GO:0032956; PAINT date 20260529. evidence: - source_id: GO_REF:0000033 statement: IBD propagation from PAINT node PTN008393484 in PTHR24072. evidence: - source_id: file:interpro/panther/PTHR24072/PTHR24072-deep-research-falcon.md title: PTHR24072 Falcon family review statement: >- Falcon family-level GO review: Over-annotation verdict for PTHR24072 (RHO FAMILY GTPASE): the current InterPro2GO state - no mapped GO terms - is APPROPRIATE and should be ACCEPTED as-is. Use this PANTHER family as context with representative members/PTN anchors, not as blanket pathway propagation. function: preferred_term: GTPase activity term: id: GO:0003924 label: GTPase activity processes: - preferred_term: chemokine-mediated signaling pathway term: id: GO:0070098 label: chemokine-mediated signaling pathway - preferred_term: cell chemotaxis term: id: GO:0060326 label: cell chemotaxis locations: - preferred_term: plasma membrane term: id: GO:0005886 label: plasma membrane - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Small Rho-family GTPase switch that coordinates actomyosin contractility, uropod retraction, and integrin avidity maturation downstream of chemokine receptor activation. evidence: - source_id: PANTHER:PTN000632671 title: PAINT node PTN000632671 for RHOA statement: >- Supports GTPase activity (GO:0003924) and actin cytoskeleton organization (GO:0007015) at the plasma membrane (GO:0005886). connections: - source: chemokine_receptor_engagement target: gi_protein_coupling connection_type: CAUSES description: >- Chemokine binding stabilizes the active conformation of CXCR1/CXCR2 or CCR5, promoting guanine nucleotide exchange on heterotrimeric Gi. - source: gi_protein_coupling target: chemotaxis_effector_output connection_type: CAUSES description: >- Released Gbetagamma and Galpha_i-GTP activate PI3Kgamma and Rho-family GTPase effectors to drive polarized leukocyte migration.