SH3BP4 promotes neuropilin-1 and ?5-integrin endocytosis and is inhibited by Akt.
Cells probe their surrounding matrix for attachment sites via integrins that are internalized by endocytosis. We find that SH3BP4 regulates integrin surface expression in a signaling-dependent manner via clathrin-coated pits (CCPs). Dephosphorylated SH3BP4 at S246 is efficiently recruited to CCPs, while upon Akt phosphorylation, SH3BP4 is sequestered by 14-3-3 adaptors ... and excluded from CCPs. In the absence of Akt activity, SH3BP4 binds GIPC1 and targets neuropilin-1 and ?5/?1-integrin for endocytosis, leading to inhibition of cell spreading. Similarly, chemorepellent semaphorin-3a binds neuropilin-1 to activate PTEN, which antagonizes Akt and thus recruits SH3BP4 to CCPs to internalize both receptors and induce cell contraction. In PTEN mutant non-small cell lung cancer cells with high Akt activity, expression of non-phosphorylatable active SH3BP4-S246A restores semaphorin-3a induced cell contraction. Thus, SH3BP4 links Akt signaling to endocytosis of NRP1 and ?5/?1-integrins to modulate cell-matrix interactions in response to intrinsic and extrinsic cues.
Mesh Terms:
14-3-3 Proteins, Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Coated Pits, Cell-Membrane, Endocytosis, Humans, Integrin alpha5, Lung Neoplasms, Mutant Proteins, Neuropilin-1, PTEN Phosphohydrolase, Protein Binding, Proto-Oncogene Proteins c-akt, Semaphorin-3A, Signal Transduction
14-3-3 Proteins, Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Coated Pits, Cell-Membrane, Endocytosis, Humans, Integrin alpha5, Lung Neoplasms, Mutant Proteins, Neuropilin-1, PTEN Phosphohydrolase, Protein Binding, Proto-Oncogene Proteins c-akt, Semaphorin-3A, Signal Transduction
Dev Cell
Date: Dec. 19, 2020
PubMed ID: 33761321
View in: Pubmed Google Scholar
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