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Rictor and integrin-linked kinase interact and regulate Akt phosphorylation and cancer cell survival.

Abstract
An unbiased proteomic screen to identify integrin-linked kinase (ILK) interactors revealed rictor as an ILK-binding protein. This finding was interesting because rictor, originally identified as a regulator of cytoskeletal dynamics, is also a component of mammalian target of rapamycin complex 2 (mTORC2), a complex implicated in Akt phosphorylation. These functions overlap with known ILK functions. Coimmunoprecipitation analyses confirmed this interaction, and ILK and rictor colocalized in membrane ruffles and leading edges of cancer cells. Yeast two-hybrid assays showed a direct interaction between the NH(2)- and COOH-terminal domains of rictor and the ILK kinase domain. Depletion of ILK and rictor in breast and prostate cancer cell lines resulted in inhibition of Akt Ser(473) phosphorylation and induction of apoptosis, whereas, in several cell lines, depletion of mTOR increased Akt phosphorylation. Akt and Ser(473)P-Akt were detected in ILK immunoprecipitates and small interfering RNA-mediated depletion of rictor, but not mTOR, inhibited the amount of Ser(473)P-Akt in the ILK complex. Expression of the NH(2)-terminal (1-398 amino acids) rictor domain also resulted in the inhibition of ILK-associated Akt Ser(473) phosphorylation. These data show that rictor regulates the ability of ILK to promote Akt phosphorylation and cancer cell survival.
AuthorsPaul C McDonald, Arusha Oloumi, Julia Mills, Iveta Dobreva, Mykola Maidan, Virginia Gray, Elizabeth D Wederell, Marcel B Bally, Leonard J Foster, Shoukat Dedhar
JournalCancer research (Cancer Res) Vol. 68 Issue 6 Pg. 1618-24 (Mar 15 2008) ISSN: 1538-7445 [Electronic] United States
PMID18339839 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Carrier Proteins
  • RICTOR protein, human
  • RNA, Small Interfering
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Serine
  • Protein Kinases
  • integrin-linked kinase
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
Topics
  • Breast Neoplasms (metabolism)
  • Carrier Proteins (genetics, metabolism)
  • Cell Line, Tumor
  • Cell Survival (physiology)
  • Chromatography, Liquid
  • Cytoskeleton (metabolism)
  • Down-Regulation
  • HeLa Cells
  • Humans
  • Immunoprecipitation
  • Neoplasms (genetics, metabolism)
  • Phosphorylation
  • Protein Binding
  • Protein Kinases (metabolism)
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • Proto-Oncogene Proteins c-akt (metabolism)
  • RNA Interference
  • RNA, Small Interfering (genetics)
  • Rapamycin-Insensitive Companion of mTOR Protein
  • Serine (metabolism)
  • TOR Serine-Threonine Kinases
  • Tandem Mass Spectrometry
  • Transfection

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