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SDF‐1 Controls Pituitary Cell Proliferation through the Activation of ERK1/2 and the Ca 2+ ‐Dependent, Cytosolic Tyrosine Kinase Pyk2
Author(s) -
MASSA ALESSANDRO,
CASAGRANDE SILVIA,
BAJETTO ADRIANA,
PORCILE CAROLA,
BARBIERI FEDERICA,
THELLUNG STEFANO,
ARENA SARA,
PATTAROZZI ALESSANDRA,
GATTI MONICA,
CORSARO ALESSANDRO,
ROBELLO MAURO,
SCHETTINI GENNARO,
FLORIO TULLIO
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1378.042
Subject(s) - intracellular , microbiology and biotechnology , chemistry , cell growth , bapta , signal transduction , cytosol , tyrosine kinase , biology , biochemistry , enzyme
Stromal cell‐derived factor‐1 (SDF‐1) is a chemokine of the CXC subfamily that exerts its effects via CXCR4, a G‐protein‐coupled receptor. CXCR4 is often expressed by tumor cells, and its activation causes tumor cell proliferation. Using GH4C1 cells, here we show that SDF‐1 induced cell proliferation in a dose‐dependent manner. Thus, we evaluated the intracellular signaling involved in this effect. SDF‐1 increased cytosolic [Ca 2+ ] and activated Pyk2, ERK1/2, and BK Ca channels. To correlate these intracellular effectors with the proliferative activity of SDF‐1, we inhibited their activity using BAPTA‐AM (Ca 2+ chelator), PD98059 (MEK inhibitor), salicylate (Pyk2 inhibitor), and TEA (K + channel blocker). All these compounds reverted SDF‐1‐induced proliferation, suggesting the involvement of multiple intracellular pathways. To identify a possible crosstalk and a molecular ordering among these pathways, we tested these antagonists on SDF‐1‐dependent activation of ERK1/2, Pyk2, and BK Ca channels. We report that the inhibition of [Ca 2+ ] i increase or the blockade of BK Ca channel activity did not affect ERK1/2 activation by SDF‐1; Pyk2 activation was purely Ca 2+ ‐dependent, not involving ERK1/2 or BK Ca channels; and BK Ca channel activity was antagonized by Pyk2 but not by ERK1/2 inhibitors. These data suggest that SDF‐1‐dependent increase of [Ca 2+ ] i activates Pyk2, which, in turn, regulates BK Ca channel activity. Conversely, ERK1/2 activation is an independent phenomenon. In conclusion, we demonstrate that SDF‐1 induces proliferation of GH4C1 cells, suggesting that the activation of CXCR4 may represent a novel regulatory mechanism for pituitary cell proliferation which may contribute to pituitary adenoma development.