Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1 cell cycle progression of intestinal epithelial cells

Zheng Fu, Jungeun Kim, Alda Vidrich, Thomas W. Sturgill, Steven Cohn

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Intestinal cell kinase (ICK), originally cloned from the intestine and expressed in the intestinal crypt epithelium, is a highly conserved serine/threonine protein kinase that is similar to mitogen-activated protein kinases (MAPKs) in the catalytic domain and requires dual phosphorylation within a MAPK-like TDY motif for full activation. Despite these similarities to MAPKs, the biological functions of ICK remain unknown. In this study, we report that suppression of ICK expression in cultured intestinal epithelial cells by short hairpin RNA (shRNA) interference significantly impaired cellular proliferation and induced features of gene expression characteristic of colonic or enterocytic differentiation. Downregulation of ICK altered expression of cell cycle regulators (cyclin D1, c-Myc, and p21Cip1/WAF1) of G1-S transition, consistent with the G1 cell cycle delay induced by ICK shRNA. ICK deficiency also led to a significant decrease in the expression and/or activity of p70 ribosomal protein S6 kinase (S6K1) and eukaryotic initiation factor 4E (eIF4E), concomitant with reduced expression of their upstream regulators, the mammalian target of rapamycin (mTOR) and the regulatory associated protein of mTOR (Raptor). Furthermore, ICK interacts with the mTOR/Raptor complex in vivo and phosphorylates Raptor in vitro. These results suggest that disrupting ICK function may downregulate protein translation of specific downstream targets of eIF4E and S6K1 such as cyclin D1 and c-Myc through the mTOR/Raptor signaling pathway. Taken together, our findings demonstrate an important role for ICK in proliferation and differentiation of intestinal epithelial cells.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume297
Issue number4
DOIs
StatePublished - Oct 13 2009
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Cell Cycle
Phosphotransferases
Epithelial Cells
TOR Serine-Threonine Kinases
Sirolimus
Mitogen-Activated Protein Kinases
Eukaryotic Initiation Factor-4E
Cyclin D1
Small Interfering RNA
Down-Regulation
Ribosomal Protein S6 Kinases
Protein-Serine-Threonine Kinases
Protein Biosynthesis
Intestinal Mucosa
RNA Interference
Intestines
Catalytic Domain
Phosphorylation
Cell Proliferation

Keywords

  • Caudaltype homeobox protein 2 (Cdx2)
  • Intestinal epithelial cell proliferation and differentiation
  • Mammalian target of rapamycin
  • Regulatory associated protein of mTOR

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Intestinal cell kinase, a MAP kinase-related kinase, regulates proliferation and G1 cell cycle progression of intestinal epithelial cells. / Fu, Zheng; Kim, Jungeun; Vidrich, Alda; Sturgill, Thomas W.; Cohn, Steven.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 297, No. 4, 13.10.2009.

Research output: Contribution to journalArticle

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