SH3BP4 promotes neuropilin-1 and α5-integrin endocytosis and is inhibited by Akt

Christoph Jakob Burckhardt, John D. Minna, Gaudenz Danuser

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 languageEnglish (US)
Pages (from-to)1164-1181.e12
JournalDevelopmental cell
Volume56
Issue number8
DOIs
StatePublished - 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
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'SH3BP4 promotes neuropilin-1 and α5-integrin endocytosis and is inhibited by Akt'. Together they form a unique fingerprint.

Cite this