Insulin receptor tyrosine kinase substrate activates EGFR/ERK signalling pathway and promotes cell proliferation of hepatocellular carcinoma

Cancer Lett. 2013 Aug 28;337(1):96-106. doi: 10.1016/j.canlet.2013.05.019. Epub 2013 May 18.


Insulin receptor tyrosine kinase substrate (IRTKS) is closely associated with actin remodelling and membrane protrusion, but its role in the pathogenesis of malignant tumours, including hepatocellular carcinoma (HCC), is still unknown. In this study, we showed that IRTKS was frequently upregulated in HCC samples, and its expression level was significantly associated with tumour size. Enforced expression of IRTKS in human HCC cell lines significantly promoted their proliferation and colony formation in vitro, and their capacity to develop tumour xenografts in vivo, whereas knockdown of IRTKS resulted in the opposite effects. Furthermore, the bromodeoxyuridine (BrdU) incorporation analyses and propidium iodide staining indicated that IRTKS can promote the entry into S phase of cell cycle progression. Significantly, IRTKS can interact with epidermal growth factor receptor (EGFR), results in the phosphorylation of extracellular signal-regulated kinase (ERK). By contrast, inhibition of ERK activation can attenuate the effects of IRTKS overexpression on cellular proliferation. Taken together, these data demonstrate that IRTKS promotes the proliferation of HCC cells by enhancing EGFR-ERK signalling pathway.

Keywords: EGFR/ERK signalling; Hepatocellular carcinoma; IRTKS; Proliferation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Carcinoma, Hepatocellular / pathology*
  • Cell Cycle
  • Cell Proliferation*
  • ErbB Receptors / physiology*
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Female
  • Humans
  • Liver Neoplasms / pathology*
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Microfilament Proteins / physiology*
  • Middle Aged
  • Signal Transduction
  • Substrate Specificity


  • BAIAP2L1 protein, human
  • Microfilament Proteins
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases