FAK-Mediated Src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation

Xiaoyang Wu; Boyi Gan; Youngdong Yoo; Jun Lin Guan

doi:10.1016/j.devcel.2005.06.006

FAK-Mediated Src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation

Xiaoyang Wu, Boyi Gan, Youngdong Yoo, Jun Lin Guan

Research output: Contribution to journal › Article › peer-review

153 Scopus citations

Abstract

Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell proliferation, survival, migration, and invasion. To understand how FAK contributes to cell invasion, we explored the regulation of matrix metalloproteinases (MMPs) by FAK. We found that v-Src-transformed cells activate a FAK-dependent mechanism that attenuates endocytosis of MT1-MMP. This in turn increases cell-surface expression of MT1-MMP and cellular degradation of extracellular matrix. Further, we identified an interaction between FAK's second Pro-rich motif and endophilin A2's SH3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow Src phosphorylation of endophilin A2 at Tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of Tyr315 phosphorylation promoted endocytosis of MT1-MMP. Together, these results suggest a regulatory mechanism of cell invasion whereby FAK promotes cell-surface presentation of MT1-MMP by inhibiting endophilin A2-dependent endocytosis.

Original language	English (US)
Pages (from-to)	185-196
Number of pages	12
Journal	Developmental cell
Volume	9
Issue number	2
DOIs	https://doi.org/10.1016/j.devcel.2005.06.006
State	Published - Aug 2005
Externally published	Yes

ASJC Scopus subject areas

Molecular Biology
General Biochemistry, Genetics and Molecular Biology
Developmental Biology
Cell Biology

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10.1016/j.devcel.2005.06.006

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@article{8bac62f3e7c74561a338aed2dcfdbaf0,

title = "FAK-Mediated Src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation",

abstract = "Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell proliferation, survival, migration, and invasion. To understand how FAK contributes to cell invasion, we explored the regulation of matrix metalloproteinases (MMPs) by FAK. We found that v-Src-transformed cells activate a FAK-dependent mechanism that attenuates endocytosis of MT1-MMP. This in turn increases cell-surface expression of MT1-MMP and cellular degradation of extracellular matrix. Further, we identified an interaction between FAK's second Pro-rich motif and endophilin A2's SH3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow Src phosphorylation of endophilin A2 at Tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of Tyr315 phosphorylation promoted endocytosis of MT1-MMP. Together, these results suggest a regulatory mechanism of cell invasion whereby FAK promotes cell-surface presentation of MT1-MMP by inhibiting endophilin A2-dependent endocytosis.",

author = "Xiaoyang Wu and Boyi Gan and Youngdong Yoo and Guan, {Jun Lin}",

note = "Funding Information: We are grateful to D. Ilic of UCSF for FAK −/− and FAK +/+ cells, P.S. McPherson of McGill University for pGEX2T-endophilin A2 plasmid, D. Shalloway of Cornell University for pMV-Src, pcDNA3-Src 527F, and pcDNA3-HA-Src527F plasmids, Rick Cerione and Ruth Collins of Cornell University for recombinant Src and Rab7 construct, respectively, D. Pei of University of Minnesota for MT1-MMP RNAi plasmid and suggestions for antibodies for MT1-MMP, and R.S. Keller of Albany Medical College for recombinant adenoviruses encoding FAK in some initial experiments. We thank our colleagues X. Peng, Z. Melkoumian, T. Stokol, and D. Rhoads for critical reading of the manuscript and helpful comments. This research was supported by NIH (GM48050) to J.-L.G. ",

year = "2005",

month = aug,

doi = "10.1016/j.devcel.2005.06.006",

language = "English (US)",

volume = "9",

pages = "185--196",

journal = "Developmental cell",

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number = "2",

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TY - JOUR

T1 - FAK-Mediated Src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation

AU - Wu, Xiaoyang

AU - Gan, Boyi

AU - Yoo, Youngdong

AU - Guan, Jun Lin

N1 - Funding Information: We are grateful to D. Ilic of UCSF for FAK −/− and FAK +/+ cells, P.S. McPherson of McGill University for pGEX2T-endophilin A2 plasmid, D. Shalloway of Cornell University for pMV-Src, pcDNA3-Src 527F, and pcDNA3-HA-Src527F plasmids, Rick Cerione and Ruth Collins of Cornell University for recombinant Src and Rab7 construct, respectively, D. Pei of University of Minnesota for MT1-MMP RNAi plasmid and suggestions for antibodies for MT1-MMP, and R.S. Keller of Albany Medical College for recombinant adenoviruses encoding FAK in some initial experiments. We thank our colleagues X. Peng, Z. Melkoumian, T. Stokol, and D. Rhoads for critical reading of the manuscript and helpful comments. This research was supported by NIH (GM48050) to J.-L.G.

PY - 2005/8

Y1 - 2005/8

N2 - Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell proliferation, survival, migration, and invasion. To understand how FAK contributes to cell invasion, we explored the regulation of matrix metalloproteinases (MMPs) by FAK. We found that v-Src-transformed cells activate a FAK-dependent mechanism that attenuates endocytosis of MT1-MMP. This in turn increases cell-surface expression of MT1-MMP and cellular degradation of extracellular matrix. Further, we identified an interaction between FAK's second Pro-rich motif and endophilin A2's SH3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow Src phosphorylation of endophilin A2 at Tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of Tyr315 phosphorylation promoted endocytosis of MT1-MMP. Together, these results suggest a regulatory mechanism of cell invasion whereby FAK promotes cell-surface presentation of MT1-MMP by inhibiting endophilin A2-dependent endocytosis.

AB - Focal adhesion kinase (FAK) is an important mediator of integrin signaling in the regulation of cell proliferation, survival, migration, and invasion. To understand how FAK contributes to cell invasion, we explored the regulation of matrix metalloproteinases (MMPs) by FAK. We found that v-Src-transformed cells activate a FAK-dependent mechanism that attenuates endocytosis of MT1-MMP. This in turn increases cell-surface expression of MT1-MMP and cellular degradation of extracellular matrix. Further, we identified an interaction between FAK's second Pro-rich motif and endophilin A2's SH3 domain. This interaction served as an autophosphorylation-dependent scaffold to allow Src phosphorylation of endophilin A2 at Tyr315. Tyr315 phosphorylation inhibited endophilin/dynamin interactions, and blockade of Tyr315 phosphorylation promoted endocytosis of MT1-MMP. Together, these results suggest a regulatory mechanism of cell invasion whereby FAK promotes cell-surface presentation of MT1-MMP by inhibiting endophilin A2-dependent endocytosis.

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FAK-Mediated Src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation

Abstract

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