Internalized CD44s splice isoform attenuates EGFR degradation by targeting Rab7A

Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8366-8371. doi: 10.1073/pnas.1701289114. Epub 2017 Jul 17.

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.

Keywords: CD44s; EGFR; GBM; Rab7A; splice isoform.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cell Line
  • Endosomes / metabolism*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism*
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • HEK293 Cells
  • Humans
  • Hyaluronan Receptors / genetics
  • Hyaluronan Receptors / metabolism*
  • Lysosomes / metabolism
  • Protein Isoforms / genetics
  • Protein Transport / genetics
  • Protein Transport / physiology
  • Signal Transduction / genetics
  • rab GTP-Binding Proteins / antagonists & inhibitors
  • rab GTP-Binding Proteins / metabolism*

Substances

  • CD44 protein, human
  • Hyaluronan Receptors
  • Protein Isoforms
  • rab7 protein
  • EGFR protein, human
  • ErbB Receptors
  • rab GTP-Binding Proteins