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*L-TYROSINE
Endocrinology Vol. 142, No. 2 564-572
Copyright © 2001 by The Endocrine Society

ARTICLES

Adrenomedullin Stimulates Proline-Rich Tyrosine Kinase 2 in Vascular Smooth Muscle Cells

Hiroaki Iwasaki, Masayoshi Shichiri, Fumiaki Marumo and Yukio Hirata

Department of Clinical and Molecular Endocrinology, Graduate School, Tokyo Medical and Dental University, Tokyo 113-0034, Japan

Address all correspondence and requests for reprints to: Yukio Hirata, M.D., Ph.D., Department of Clinical and Molecular Endocrinology (the Second Department of Internal Medicine), Graduate School, Tokyo Medical and Dental University, 1–5-45, Yushima, Bunkyo-ku, Tokyo 113-0034, Japan. E-mail: yhirata.cme{at}tmd.ac.jp

A novel vasodilator peptide, adrenomedullin (AM) stimulates extracellular signal-regulated kinase (ERK) 1/2 via yet uncharacterized 120 kDa tyrosine kinase(s) in rat vascular smooth muscle cells (VSMC). In the present study, we have examined whether the AM-activated tyrosine kinase is proline-rich tyrosine kinase 2 (PYK2) associable with adapter proteins. AM rapidly (within 30 sec) and dose dependently increased tyrosine kinase activity, whose effect was enhanced in the presence of o-vanadate, a phosphatase inhibitor. A tyrosine kinase with an apparent molecular mass of 120 kDa corresponding to that of PYK2 was predominantly localized to the cytosolic fraction, whereas the tyrosine-phosphorylated 180-kDa protein was observed in the membrane fraction from EGF-treated cells, but not from AM-treated cells. AM induced rapid (within 30 sec) and transient phosphorylation of PYK2, but not focal adhesion kinase. AM caused autophosphorylation of tyrosine residue(s) of PYK2 and promoted its association with adaptor proteins (Shc/Grb2). AM rapidly (within 1 min) activated c-Src and enhanced its association with tyrosine-phosphorylated PYK2. These data suggest that AM stimulates PYK2 which, in turn, activates c-Src and induces recruitment of adaptor proteins (Shc/Grb2), thereby leading to activation of p21ras/ERK1/2 cascade in VSMC.




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