c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway

Wook Jin, Chohee Yun, Joon Jeong, Yangho Park, Hy De Lee, Seong Jin Kim

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

TrkC mediates many aspects of growth and development in the central nervous system. TrkC is expressed in a variety of non-neuronal tissues as well as human cancers. TrkC overexpression may drive tumorigenesis, invasion, and metastatic capability in cancer cells. However, relatively little is known about whether TrkC activity is also essential to maintain the malignant properties in human tumors. TrkC expression leads to the constitutive activation of two major effector pathways, namely the Ras-MAP kinase (MAPK) mitogenic pathway and the phosphatidylinositol 3-kinase (PI3K)-AKT pathway mediating cell survival. However, it remains unclear how TrkC activates Ras-Erk1/2 and/or PI3K-Akt cascades. Here we define some aspects of the molecular mechanisms regulating TrkC-dependent Ras-Erk1/2 and PI3K/Akt activation. We show that endogenous TrkC associated with c-Src in human and mouse cancer cells which express TrkC. TrkC-c-Src complexes were also detected in primary human breast cancer tissues. Suppression of c-Src by RNA interference in highly metastatic 4T1 mammary cancer cells, which express endogenous TrkC, resulted in markedly decreased expression of cyclin D1 and suppression of activation of Ras-Erk1/2 and PI3K-Akt. Moreover, inhibition of c-Src expression almost completely blocks colony formation of 4T1 cells in soft agar. Furthermore, in c-Src-deficient SYF cells, TrkC failed to activate the PI3K-Atk pathway, but not the Ras-Erk1/2 pathway. Therefore these data indicate that TrkC induces the PI3K-Akt cascade through the activation of c-Src.

Original languageEnglish
Pages (from-to)1391-1400
Number of pages10
JournalJournal of Biological Chemistry
Volume283
Issue number3
DOIs
Publication statusPublished - 2008 Jan 18

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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