Abstract
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 α5/β1-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 α5/β1-integrins to modulate cell-matrix interactions in response to intrinsic and extrinsic cues.
Original language | English (US) |
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Pages (from-to) | 1164-1181.e12 |
Journal | Developmental cell |
Volume | 56 |
Issue number | 8 |
DOIs | |
State | Published - Apr 19 2021 |
Keywords
- Akt
- GIPC1
- NRP1
- NSCLC
- PTEN
- SH3BP4
- Semaphorin-3a
- alpha-5-integrin
- clathrin-mediated endocytosis
- non-small cell lung cancer
ASJC Scopus subject areas
- Molecular Biology
- General Biochemistry, Genetics and Molecular Biology
- Developmental Biology
- Cell Biology