Intracellular acidosis activates c-Src

Abstract

The purpose of the present studies was to determine whether acidosis activates protein tyrosine kinase pathways. Incubation of MCT cells, a renal proximal tubule cell line, in acid media caused increased phosphotyrosine content of 60- to 70- and 120-kDa cytosolic proteins. Media acidification induced a twofold increase in c-Src activity that occurred within 30 s. Significant activation occurred with media pH changes as small as 0.07 pH unit accompanied by cell acidification of 0.06 pH unit. Sodium propionate addition, NH4Cl prepulse, and nigericin addition, maneuvers that decrease intracellular pH in the absence of changes in extracellular pH, activated c-Src. Significant activation by sodium propionate was seen with cell pH changes as small as 0.07 pH unit. Sodium orthovanadate, a protein tyrosine phosphatase inhibitor, prevented c-Src activation by media acidification but did not prevent protein tyrosine phosphorylation. In summary, decreased intracellular pH activates c-Src. Acid activation of c-Src represents a novel mechanism of c-Src activation that may be relevant to many cellular responses to acidosis.

Acid sensing in renal epithelial cells

“…A subsequent study identified the proto-oncogene c-Src as the cellular tyrosine kinase essential for this response (17). Activation of c-Src tyrosine kinase (herein referred to as c-Src) requires phosphorylation on an internal tyrosine residue, and changes in extracellular pH of 0.07 (equivalent to a change in bicarbonate concentration of 3-4 mM) were found to induce a detectable increase in phosphorylation of c-Src (18). Surprisingly, the phosphorylation of c-Src was greatest after only 90 seconds of cellular acidification, subsequently returning to a level slightly above baseline.…”

Promotion of osteoclast differentiation and activation in spite of impeded osteoblast-lineage differentiation under acidosis: Effects of acidosis on bone metabolism

“…The mice also showed defects in osteoclast formation and activity, with large osteoclasts small in number (28). TRPV4 shows a weak response to acid (29), and is activated by src under acidotic conditions (30), implying that TRPV4 could be activated during acidosis.…”

Na+/H+ Exchangers in Renal Regulation of Acid-Base Balance

“…Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity. [59][60][61][62] Downstream from c-Src is endothelin-1 (ET-1) production and secretion by the proximal tubule. 53,63 The mechanism by which c-Src stimulates ET-1 secretion is not yet known.…”

“…Both Pyk2 and c-Src activation are required for acid to activate NHE3 activity. [59][60][61][62] Downstream from c-Src is endothelin-1 (ET-1) production and ET-1/ETB mediates acid stimulation of NHE3 involving exocytic insertion of NHE3 into the apical membrane. This process requires an intact cytoskeleton, 65 and is associated with NHE3 phosphorylation.…”