@article{6da97ed9ecf64ab49040e871d33db751,
title = "SH3BP4 promotes neuropilin-1 and α5-integrin endocytosis and is inhibited by Akt",
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.",
keywords = "Akt, GIPC1, NRP1, NSCLC, PTEN, SH3BP4, Semaphorin-3a, alpha-5-integrin, clathrin-mediated endocytosis, non-small cell lung cancer",
author = "Burckhardt, {Christoph J.} and Minna, {John D.} and Gaudenz Danuser",
note = "Funding Information: We thank Sandra Schmid for guidance on endocytosis experiments and for critically reading the manuscript. We thank members of the Danuser lab for helpful discussions. We thank Ross Tomaino from the Taplin Mass Spectrometry Facility at the Department of Cell Biology Cell Biology at Harvard Medical School for expert analysis. We thank Luc Girard for genomic analyses of lung cancer lines. We thank Nicolas Loof for support with cell sorting/flow cytometry analysis for this project on instruments in the Moody Foundation Flow Cytometry Facility at UT Southwestern Medical Center. This project was supported by the Swiss National Science Foundation (SNF, PA00P3_139694) and the Novartis Research Foundation (both to C.J.B.). Funding in the Danuser lab for this work was made available through NIH grants GM067230, GM073165, and GM136428. This work was supported by NIH Lung SPORE grant P50 CA070907 (J.D.M.). C.J.B. conceived and designed the study and executed all experiments and analyses with overall scientific observation by G.D.; C.J.B. wrote the manuscript with substantial edits by G.D.; J.D.M. provided reagents, scientific guidance, and critical insights. The authors declare no competing interests. G.D. is a member of the editorial board of Developmental Cell. Funding Information: We thank Sandra Schmid for guidance on endocytosis experiments and for critically reading the manuscript. We thank members of the Danuser lab for helpful discussions. We thank Ross Tomaino from the Taplin Mass Spectrometry Facility at the Department of Cell Biology Cell Biology at Harvard Medical School for expert analysis. We thank Luc Girard for genomic analyses of lung cancer lines. We thank Nicolas Loof for support with cell sorting/flow cytometry analysis for this project on instruments in the Moody Foundation Flow Cytometry Facility at UT Southwestern Medical Center. This project was supported by the Swiss National Science Foundation (SNF, PA00P3_139694 ) and the Novartis Research Foundation (both to C.J.B.). Funding in the Danuser lab for this work was made available through NIH grants GM067230 , GM073165 , and GM136428 . This work was supported by NIH Lung SPORE grant P50 CA070907 (J.D.M.). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = apr,
day = "19",
doi = "10.1016/j.devcel.2021.03.009",
language = "English (US)",
volume = "56",
pages = "1164--1181.e12",
journal = "Developmental Cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "8",
}