Vasopressin-mediated mitogenic signaling in intestinal epithelial cells

Terence Chiu, Steven S. Wu, Chintda Santiskulvong, Pisit Tangkijvanich, Hal F. Yee Jr., Enrique Rozengurt


The role of G protein-coupled receptors and their ligands in intestinal epithelial cell signaling and proliferation is poorly understood. Here, we demonstrate that arginine vasopressin (AVP) induces multiple intracellular signal transduction pathways in rat intestinal epithelial IEC-18 cells via a V1A receptor. Addition of AVP to these cells induces a rapid and transient increase in cytosolic Ca2+concentration and promotes protein kinase D (PKD) activation through a protein kinase C (PKC)-dependent pathway, as revealed by in vitro kinase assays and immunoblotting with an antibody that recognizes autophosphorylated PKD at Ser916. AVP also stimulates the tyrosine phosphorylation of the nonreceptor tyrosine kinase proline-rich tyrosine kinase 2 (Pyk2) and promotes Src family kinase phosphorylation at Tyr418, indicative of Src activation. AVP induces extracellular signal-related kinase (ERK)-1 (p44mapk) and ERK-2 (p42mapk) activation, a response prevented by treatment with mitogen-activated protein kinase kinase (MEK) inhibitors (PD-98059 and U-0126), specific PKC inhibitors (GF-I and Ro-31-8220), depletion of Ca2+ (EGTA and thapsigargin), selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (tyrphostin AG-1478, compound 56), or the selective Src family kinase inhibitor PP-2. Furthermore, AVP acts as a potent growth factor for IEC-18 cells, inducing DNA synthesis and cell proliferation through ERK-, Ca2+-, PKC-, EGFR tyrosine kinase-, and Src-dependent pathways.

  • arginine vasopressin
  • protein kinase D
  • protein kinase C
  • Src
  • proline-rich tyrosine kinase 2
  • intestinal epithelial proliferation


  • This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases Grants DK-55003 and DK-56930 to E. Rozengurt. T. Chiu is a recipient of an American Gastroenterological Association (AGA)-AstraZeneca Fellowship/Faculty Transition Award. S. S. Wu is a National Institutes of Health Fellow of the Pediatric Scientist Development Program (K12-HD-00850).

  • Address for reprint requests and other correspondence: E. Rozengurt, 900 Veteran Ave., Warren Hall, Rm. 11–124, Dept. of Medicine, UCLA School of Medicine, Los Angeles, CA 90095-1786 (E-mail:erozengurt{at}

  • The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • 10.1152/ajpcell.00240.2001

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