High calcium activates the EGF receptor potentially through the calcium-sensing receptor in Leydig cancer cells

Growth Factors. 2005 Jun;23(2):117-23. doi: 10.1080/08977190500126272.


Epidermal growth factor (EGF) plays an important role in the physiology and pathophysiology of the Leydig cell. In H-500 rat Leydig cancer cells, a model for humoral hypercalcemia of malignancy (HHM), we previously showed that the calcium-sensing receptor (CaR) stimulates PTHrP release and proliferation, both involving multiple mitogen-activated protein kinases. An emerging concept of signaling by G-protein coupled receptors (GPCR) is that it occurs via transactivation of receptor tyrosine kinases. Therefore, we investigated whether stimulation with calcium activates the EGFR in H-500 Leydig cancer cells. We show that treatment of H-500 cells with Ca(2+) results in EGFR phosphorylation. The CaR-induced activation of ERK1/2, induction of PTHrP release and stimulation of cellular proliferation in H-500 cells are likewise mediated, in large part, through the EGFR. In conclusion, the calcium activates the EGFR, possibly through the CaR, to regulate downstream signaling events and important biological functions in a model of HHM.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blotting, Western
  • Calcium / metabolism*
  • Cell Line, Tumor
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • ErbB Receptors / metabolism*
  • Gene Expression Regulation, Neoplastic*
  • Immunoprecipitation
  • Leydig Cells / pathology
  • MAP Kinase Signaling System
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Parathyroid Hormone-Related Protein / metabolism
  • Phosphorylation
  • Rats
  • Receptors, Calcium-Sensing / metabolism*
  • Signal Transduction
  • Testicular Neoplasms / metabolism*
  • Transcriptional Activation


  • Parathyroid Hormone-Related Protein
  • Receptors, Calcium-Sensing
  • ErbB Receptors
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Calcium