Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A

Wei Wang; Honghong Zhang; Sali Liu; Chung Kwon Kim; Yilin Xu; Lisa A. Hurley; Ryo Nishikawa; Motoo Nagane; Bo Hu; Alexander H. Stegh; Shi Yuan Cheng; Chonghui Cheng

doi:10.1073/pnas.1701289114

Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A

Wei Wang, Honghong Zhang, Sali Liu, Chung Kwon Kim, Yilin Xu, Lisa A. Hurley, Ryo Nishikawa, Motoo Nagane, Bo Hu, Alexander H. Stegh, Shi Yuan Cheng, Chonghui Cheng

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

34 Scopus citations

Abstract

CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.

Original language	English
Pages (from-to)	8366-8371
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	114
Issue number	31
DOIs	https://doi.org/10.1073/pnas.1701289114
State	Published - Aug 1 2017

Keywords

CD44s
EGFR
GBM
Rab7A
Splice isoform

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10.1073/pnas.1701289114

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Wang, W., Zhang, H., Liu, S., Kim, C. K., Xu, Y., Hurley, L. A., Nishikawa, R., Nagane, M., Hu, B., Stegh, A. H., Cheng, S. Y., & Cheng, C. (2017). Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A. Proceedings of the National Academy of Sciences of the United States of America, 114(31), 8366-8371. https://doi.org/10.1073/pnas.1701289114

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abstract = "CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.",

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AU - Wang, Wei

AU - Zhang, Honghong

AU - Liu, Sali

AU - Kim, Chung Kwon

AU - Xu, Yilin

AU - Hurley, Lisa A.

AU - Nishikawa, Ryo

AU - Nagane, Motoo

AU - Hu, Bo

AU - Stegh, Alexander H.

AU - Cheng, Shi Yuan

AU - Cheng, Chonghui

PY - 2017/8/1

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AB - CD44 has been postulated as a cell surface coreceptor for augmenting receptor tyrosine kinase (RTK) signaling. However, how exactly CD44 triggers RTK-dependent signaling remained largely unclear. Here we report an unexpected mechanism by which the CD44s splice isoform is internalized into endosomes to attenuate EGFR degradation. We identify a CD44s-interacting small GTPase, Rab7A, and show that CD44s inhibits Rab7A-mediated EGFR trafficking to lysosomes and subsequent degradation. Importantly, CD44s levels correlate with EGFR signature and predict poor prognosis in glioblastomas. Because Rab7A facilitates trafficking of many RTKs to lysosomes, our findings identify CD44s as a Rab7A regulator to attenuate RTK degradation.

KW - CD44s

KW - EGFR

KW - GBM

KW - Rab7A

KW - Splice isoform

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JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

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Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A

Abstract

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