PKC/Src ACTIVATION MEDIATE 1,25(OH)2D3 AND 17b-ESTRADIOL REGULATION OF MAPK PATHWAYS IN MUSCLE CELLS

RONDA ANA CAROLINA; BUITRAGO CLAUDIA; BOLAND RICARDO

ROSARIO, SANTA FE, ARGENTINA

Congreso; SAIB 4XLII REUNIÓN ANUAL; 2006

SOCIEDAD ARGENTINA DE INVESTIGACIÓN EN BIOQUÍMICA Y BIOLOGÍA MOLECULAR

The mitogen activated protein kinases (MAPKs) are a superfamily, among which ERK 1/2 and p38 MAPK have been extensively studied.1a,25-dihydroxy-vitamin D3 (1a,25(OH)2D3) and 17b-estradiol promote biological responses through MAPK cascades in various cell types. We have previously shown that these steroid hormones stimulate the phosphorylation of transcription factors Elk-1 and CREB via the ERK 1/2 and p38 MAPK pathways in the skeletal muscle cell line C2C12. Now, we have studied  upstream steps involved in modulation of MAPK cascades in these cells. Our results demonstrate that 1a,25(OH)2D3 and 17b-estradiol activate the non-receptor protein tyrosine kinase c-Src at 60 and 15 minutes, respectively. Moreover, specific inhibition with compound PP1 or knock-down with antisense oligonucleotides  revealed the participation of c-Src in ERK 1/2 and p38 MAPK phosphorylation induced by the two hormones. We observed that 1a,25(OH)2D3 and 17b-estradiol modulate Src activation in a PKC-dependent manner, possibly through a protein tyrosine phosphatase (PTPa). We conclude that 1a,25(OH)2D3 and 17b-estradiol act upstream on mitogenic cascades sequentially activating PKC, c-Src via a PTP,  and finally ERK1/2 and p38 MAPK. This mechanism is congruent with the anabolic action of both hormones in muscle tissue.