Involvement of Integrins and Src in Insulin Signaling toward Autophagic Proteolysis in Rat Liver

Extracellular matrix regulation of autophagy

“…Upon hypoosmotic swelling in rat liver, cell volume is reduced in part by pathways that inhibit autophagic proteolysis. Inhibiting integrin engagement using an RGD-containing peptide antagonist prevents this reduction in autophagic proteolysis typically seen in hypoosmotic conditions [18,19]. These studies delineated an inverse role between integrin engagement and autophagy induction.…”

The Src family kinases: distinct functions of c-Src, Yes, and Fyn in the liver

“…EGFR activation by insulin was sensitive to bumetanide (which prevents insulin-induced hepatocyte swelling) and to inhibition by an integrin-antagonistic RGD peptide, an integrin β 1 subunit-blocking antibody, and the Src family kinase inhibitor PP-2. These findings point to an important role of the recently described swelling-induced and integrin-dependent osmo-sensing/osmo-signaling pathway in insulin signaling [detailed description see above (18,37) ]. Both insulin and hypoosmolarity induced a significant increase in BrdU uptake in primary rat hepatocytes suggestive of hepatocyte proliferation, which was again sensitive to inhibition by a RGD motif containing hexapeptide, an integrin β 1 -blocking antibody, the Src kinase inhibitor PP-2, AG1478, and PD 98059, suggestive of an involvement of α 5 β 1 -integrins, c-Src, EGFR, and Erk-1/-2 (18) .…”

“…Here, the regulation of liver cell function by changes in hepatocyte volume, which reflect on short-term time scale changes in hepatocyte hydration, requires structures, which pick up changes in liver cell volume (osmo-sensing) and which further signal this information toward effector sites (osmo-signaling). Our own studies identified the integrin system as a major osmosensor in hepatocytes (18,31,37) . Integrins are a family of extracellular matrix (ECM) adhesion molecules involved in ' mechanotransduction ' and growth factor signaling (38 -40) .…”

“…Also, cell swelling induced by insulin triggers an α 5 β 1 integrin-dependent activation of FAK, c-Src, Erks, and p38 MAPK , the latter of which mediates the anti-proteolytic effect of insulin (37) . Apart from its metabolic effects, insulin stimulates proliferation in the liver and other organs (102 -104) .…”

“…As shown recently, hypoosmotic swelling of hepatocytes induces a rapid activation of the β 1 integrin subunit in the plasma membrane (18) . Also, hepatocyte cell swelling induced by insulin activates the β 1 integrins in the plasma membrane (37) . Interestingly, the choleretic and anti-apoptotic bile acid tauroursodeoxycholate (TUDC) and urea can induce direct β 1 integrin activation in hepatocytes without triggering hepatocyte swelling (44,45) .…”