SH3PXD2B

SH3PXD2B (TKS4) is a Src-phosphorylated scaffold protein that drives podosome assembly, ECM degradation, and cell migration through its PX domain and four SH3 domains. It localizes to podosomes in Src-transformed cells, where it is required for complete podosome rosette formation and recruitment of MT1-MMP; its tyrosine phosphorylation by Src is essential for these functions (PMID:19144821). SH3PXD2B interacts with cortactin and ADAM15 at podosomes and EGF-induced lamellipodia, and its loss impairs lamellipodia formation, cell spreading, and pericellular collagen remodeling, leading to fibrosis in vivo (PMID:21886807, PMID:33234702). Loss-of-function mutations in SH3PXD2B cause Frank-Ter Haar syndrome, a developmental disorder affecting skeletal, cardiovascular, and ocular tissues, as confirmed by human genetics and recapitulation in Tks4-null mice (PMID:20137777).

1. 2009 High

   Establishing SH3PXD2B as a Src substrate required for podosome integrity and ECM degradation resolved how invadopodia/podosome scaffolding depends on tyrosine phosphorylation-driven adaptor recruitment.

   Evidence shRNA knockdown and Tks4-null MEFs with rescue by WT and phospho-mutant constructs, ECM degradation assays, immunofluorescence for MT1-MMP recruitment

   PMID:19144821

   Open questions at the time

   • Identity of the kinase-specific phosphotyrosine sites required for each downstream function not fully mapped
   • Mechanism by which SH3PXD2B recruits MT1-MMP to podosomes not defined at the structural level
   • Relative contributions of the PX domain versus SH3 domains to podosome targeting not dissected
2. 2009 Medium

   Identification of ADAM15 as a binding partner of the fourth SH3 domain extended the podosome scaffold model to include transmembrane metalloproteinases beyond MT1-MMP.

   Evidence Co-immunoprecipitation and SH3 domain pulldown in Src-transfected fibroblasts

   PMID:19669234

   Open questions at the time

   • Functional consequence of the SH3PXD2B–ADAM15 interaction on ECM degradation not tested
   • No reciprocal validation or endogenous co-IP reported
   • Whether ADAM15 localizes to podosomes in an SH3PXD2B-dependent manner is untested
3. 2010 High

   Linking SH3PXD2B loss-of-function to Frank-Ter Haar syndrome established a direct developmental requirement for podosome-mediated ECM remodeling in skeletal, cardiac, and ocular morphogenesis.

   Evidence Homozygosity mapping and sequencing in multiple FTHS families identifying five homozygous mutations; Tks4-null mice recapitulating FTHS phenotypes

   PMID:20137777

   Open questions at the time

   • Cell-type-specific contributions of SH3PXD2B to each affected organ system not resolved
   • Whether residual podosome function from TKS5 (SH3PXD2A) partially compensates in FTHS patients is unknown
4. 2011 Medium

   Demonstrating that SH3PXD2B complexes with both Src and cortactin and is required for EGF-induced lamellipodia broadened its role from a podosome-restricted scaffold to a general actin-based protrusion regulator.

   Evidence Reciprocal co-immunoprecipitation of SH3PXD2B with Src and cortactin; siRNA knockdown with lamellipodia formation and cell spreading assays

   PMID:21886807

   Open questions at the time

   • Whether SH3PXD2B directly bridges Src to cortactin or forms separate binary complexes is unresolved
   • Signaling intermediates between EGF receptor and SH3PXD2B activation not identified
5. 2020 Medium

   Zebrafish sh3pxd2b mutants revealed that SH3PXD2B-dependent podosome function is specifically required for collagen remodeling and fibrosis prevention, acting in a pathway distinct from MMP14.

   Evidence sh3pxd2b loss-of-function zebrafish (pretzel) with histological fibrosis analysis and phenotypic comparison to mmp14a/b knockouts

   PMID:33234702

   Open questions at the time

   • Molecular basis for the distinct spatiotemporal requirements of SH3PXD2B versus MMP14 in ECM remodeling is undefined
   • Whether fibrosis arises from failed collagen turnover or aberrant collagen deposition is not distinguished
   • Rescue experiments with mammalian SH3PXD2B in zebrafish not performed

• Key unresolved questions include the structural basis of SH3PXD2B scaffold assembly at podosomes, the full inventory of SH3 domain-dependent interactors, and how SH3PXD2B coordinates with TKS5 to regulate invadopodia versus podosomes in different cell types.
• No high-resolution structural data for SH3PXD2B or its domain complexes
• Functional redundancy versus division of labor with TKS5/SH3PXD2A not systematically tested
• Role in cancer cell invasion established only at preprint level without peer-reviewed validation