Stimulation of Mitogen-activated Protein Kinase and Na+/H+ Exchanger in Human Platelets

Abstract

Platelets are terminally differentiated cells that exhibit rapid phosphorylation of many proteins upon agonist-induced activation. Thus, platelets are a good model system to study signal transduction events that are not regulated by gene expression of proteins.Mitogen-activated protein kinases (MAPKs) 1 comprise a family of 40 -45-kDa protein serine/threonine kinases that are activated by many extracellular stimuli, including growth factors and hormones. MAPKs require phosphorylation on both threonine and tyrosine residues in the sequence Thr 183

Rapid activation of sodium–proton exchange and extracellular signal-regulated protein kinase in fibroblasts by G protein-coupled 5-HT1A receptor involves distinct signalling cascades

“…Those similarities provide evidence to suggest that ERK may be a direct proximal component of an NHE regulatory pathway [5,6]. There is a growing awareness that tyrosine phosphorylation cycles are critical in regulating NHE activities in a number of cell types [6][7][8][9][10], as has also been shown for ERK [11]. Other studies have demonstrated that NHE and ERK activities are modulated by overlapping upstream enzymes, including phosphoinositide 3h-kinase (PI-3K), phospholipase Cγ, and PKC [12][13][14][15][16][17][18][19].…”

“…Moreover, the signal initiated by AVP was sensitive to genistein, a broad-spectrum inhibitor of tyrosine kinases [6]. The study of Aharonovitz and Granot [6] specifically supported a role for MEK and a tyrosine kinase in the activation of platelet NHE by AVP, but did not address the role of other molecules in the ERK cascade in this process. More recently, Bianchini et al [25] presented data to support a role for ERK in activating NHE type 1 in fibroblast cells.…”

“…Those stimuli include, but are not limited to : growth factors that modulate tyrosine phosphorylation cycles, integrins, hyperosmotic stress or cell shrinkage, protein kinase C (PKC), tyrosine phosphorylation cascades and heterotrimeric G proteins [1][2][3][4]. Those similarities provide evidence to suggest that ERK may be a direct proximal component of an NHE regulatory pathway [5,6]. There is a growing awareness that tyrosine phosphorylation cycles are critical in regulating NHE activities in a number of cell types [6][7][8][9][10], as has also been shown for ERK [11].…”

“…enzymes, tyrosine kinases, and NHEs as playing interrelated roles along with ERK in cell growth [2,5,6,11,20].…”

“…The possibility that ERK rapidly regulates NHE activity was recently tested in platelets by Aharonovitz and Granot [6], who showed that arginine vasopressin (AVP) and PMA rapidly activated NHE by a pathway which was sensitive to PD98059, a specific inhibitor of MEK1. Moreover, the signal initiated by AVP was sensitive to genistein, a broad-spectrum inhibitor of tyrosine kinases [6].…”