PPFIBP1

PPFIBP1 (liprin-β1) is a multivalent scaffold protein that heterodimerizes with liprin-α family members through its C-terminal non-coiled-coil region and homodimerizes via its N-terminal coiled-coil domain, functioning to localize LAR-family receptor tyrosine phosphatases at specific plasma membrane sites (PMID:9624153). It is a component of cortical microtubule attachment complexes containing KANK1, liprin-α1, and LL5β, linking it to regulation of microtubule dynamics at the cell periphery (PMID:24120883). In glioma cells, PPFIBP1 promotes migration and invasion by interacting with SRCIN1 and activating FAK/Src/JNK/c-Jun signaling to upregulate MMP-2 expression, and its overexpression enhances tumor infiltration and reduces survival in xenograft models (PMID:34480020).

1. 1998 High

   The founding question of how LAR-family receptor phosphatases are localized at the plasma membrane was answered by identifying PPFIBP1 (liprin-β1) as a member of the liprin family that heterodimerizes with liprin-α proteins and participates in LAR clustering, establishing the multivalent scaffold model for phosphatase localization.

   Evidence Yeast two-hybrid, co-immunoprecipitation, domain mapping, and co-expression localization studies

   PMID:9624153

   Open questions at the time

   • Whether liprin-β1 directly contacts LAR or only bridges via liprin-α remains unresolved
   • No structural data for the liprin-β1/liprin-α interface
   • Functional consequence of liprin-β1 loss on LAR signaling was not tested
2. 2011 Medium

   Placing PPFIBP1 within cortical microtubule attachment complexes containing KANK1, liprin-α1, and LL5β expanded its functional context from phosphatase scaffolding to regulation of microtubule capture at the cell periphery, while proteomic detection in focal adhesions linked it to the mechanosensitive adhesion compartment.

   Evidence Affinity proteomics, co-immunoprecipitation, confocal microscopy, and quantitative focal adhesion proteomics

   PMID:21423176 PMID:24120883

   Open questions at the time

   • The specific functional contribution of PPFIBP1 to cortical microtubule attachment was not individually dissected
   • Focal adhesion detection was proteomics-based without direct functional follow-up for PPFIBP1
   • Whether PPFIBP1's role in cortical complexes is independent of its LAR-scaffolding function is unknown
3. 2011 High

   Identification of the PPFIBP1-ALK fusion in inflammatory myofibroblastic tumor demonstrated that the PPFIBP1 locus can serve as an oncogenic fusion partner, with the chimeric protein showing transforming activity both in vitro and in vivo.

   Evidence 5'-RACE, RT-PCR, FISH confirmation, NIH 3T3 focus formation assay, and in vivo tumorigenicity assay

   PMID:21430068

   Open questions at the time

   • Whether the coiled-coil domain of PPFIBP1 drives constitutive dimerization of the fusion kinase was not tested
   • Prevalence of this fusion across tumor types beyond IMT is not established in this study
4. 2021 High

   The mechanism by which PPFIBP1 promotes cancer cell invasion was resolved: interaction with SRCIN1 activates FAK/Src/JNK/c-Jun signaling, upregulating MMP-2 and driving glioma cell migration, invasion, and in vivo tumor infiltration.

   Evidence Knockdown/overexpression, transwell and scratch assays, co-immunoprecipitation with SRCIN1, pharmacological pathway inhibition, and xenograft models in glioma cells

   PMID:34480020

   Open questions at the time

   • Whether the SRCIN1–FAK/Src axis operates in non-glioma contexts is untested
   • The structural basis of the PPFIBP1–SRCIN1 interaction is unknown
   • Relationship between the LAR-scaffolding and SRCIN1-mediated invasion functions has not been explored

• How PPFIBP1's distinct interaction networks—LAR phosphatase scaffolding, cortical microtubule attachment, and SRCIN1-mediated invasion signaling—are coordinated or segregated in different cellular contexts remains an open question.
• No structure of PPFIBP1 or its complexes is available
• Whether liprin-β1 has catalytic or enzymatic activity independent of scaffolding is unknown
• Tissue-specific functions and knockout phenotypes in mammalian models are poorly characterized