Ly. Rui et al., Platelet-derived growth factor and lysophosphatidic acid inhibit growth hormone binding and signaling via a protein kinase C-dependent pathway, J BIOL CHEM, 275(4), 2000, pp. 2885-2892
Growth hormone (GH) regulates body growth and metabolism. GH exerts its bio
logical action by stimulating JAK2, a GH receptor (GHR)-associated tyrosine
kinase. Activated JAK2 phosphorylates itself and GHR, thus initiating mult
iple signaling pathways. In this work, we demonstrate that platelet-derived
growth factor (PDGF) and lysophosphatidic acid (LPA) down-regulate GH sign
aling via a protein kinase C (PKC)-dependent pathway. PDGF substantially re
duces tyrosyl phosphorylation of JAK2 induced by GH but not interferon-gamm
a or leukemia inhibitory factor. PDGF, but not epidermal growth factor, dec
reases tyrosyl phosphorylation of GHR (by approximately 90%) and the amount
of both total cellular GHR (by approximately 80%) and GH binding (by appro
ximately 70%). The inhibitory effect of PDGF on GH-induced tyrosyl phosphor
ylation of JAK2 and GHR is abolished by depletion of 4 beta-phorbol 12-myri
state 13-acetate (PMA)-sensitive PKCs with chronic PMA treatment and is sev
erely inhibited by GF109203X, an inhibitor of PKCs. In contrast, extracellu
lar signal-regulated kinases I and 2 and phosphatidylinositol S-kinase appe
ar not to be involved in this inhibitory effect of PDGF. LPA, a known activ
ator of PKC, also inhibits GH-induced tyrosyl phosphorylation of JAK2 and G
HR and reduces the number of GHR. We propose that ligands that activate PKC
, including PDGF, LPA, and PMA, down-regulate GH signaling by decreasing th
e number of cell surface GHR through promoting GHR internalization and degr
adation and/or cleavage of membrane GHR and release of the extracellular do
main of GHR.