Extracellular calcium-sensing receptor transactivates the epidermal growth factor receptor by a triple-membrane-spanning signaling mechanism.
Activation of the extracellular calcium-sensing receptor (CaR) stimulates mitogen-activated protein kinases to upregulate the synthesis and secretion of parathyroid hormone related peptide (PTHrP) from cells expressing the CaR heterologously or endogenously. The current experiments demonstrate that this occurs because CaR activation "transactivates" the EGF receptor (EGFR). Time dependent increases in tyrosine phosphorylation of the EGFR after addition of extracellular calcium ([Ca2+]o, 3 mM) occurred in stably CaR-transfected HEK293 cells but not in non-transfected HEK293 cells. AG1478, an EGFR kinase inhibitor, prevented the CaR-mediated increases of pERK and PTHrP release, while AG1296, a PDGFR kinase inhibitor, had no effect. Inhibitors of matrix metalloproteinase and heparin bound-EGF prevented the CaR-mediated increases of pERK and PTHrP, consistent with a "triple-membrane-spanning signaling" requirement for transactivation of the EGFR by the CaR. Proximal and distal signal transduction cascades activated by the CaR may reflect transactivation of the EGFR by the extracellular calcium-sensing receptor.
MacLeod
R John
RJ
Endocrine-Hypertension Division and Membrane Biology Program, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. macleodj@HDH.KARI.NET
Yano
S
S
Chattopadhyay
N
N
Brown
E M
EM
D002460:Cell Line; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D010766:Phosphorylation; D011799:Quinazolines; D044169:Receptors, Calcium-Sensing / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins / Q000494:pharmacology
D004791:Enzyme Inhibitors; D011799:Quinazolines; D044169:Receptors, Calcium-Sensing; D020032:Tyrphostins; C101044:RTKI cpd; D014443:Tyrosine; D066246:ErbB Receptors