Choice of STATs and Other Substrates Specified by Modular Tyrosine-Based Motifs in Cytokine Receptors

Abstract

Many members of the cytokine receptor superfamily initiate intracellular signaling by activating members of the Jak family of tyrosine kinases. Activation of the same Jaks by multiple cytokines raises the question of how these cytokines activate distinct intracellular signaling pathways. Selection of particular substrates--the transcriptional activator Stat3 and protein tyrosine phosphatase PTP1D--that characterize responses to the ciliary neurotrophic factor-interleukin-6 cytokine family depended not on which Jak was activated, but was instead determined by specific tyrosine-based motifs in the receptor components--gp130 and LIFR--shared by these cytokines. Further, these tyrosine-based motifs were modular, because addition of a Stat3-specifying motif to another cytokine receptor, that for erythropoietin, caused it to activate Stat3 in a ligand-dependent fashion.

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

“…We and others have previously shown that the addition of`tyrosine modules' from gp130 or from other receptors to the membrane proximal region of gp130 resulted in receptors capable of activating STATs Stahl et al, 1995). We therefore generated clones expressing chimeric receptor constructs with tyrosine modules Y767 or Y814 from gp130 ( Figure 3).…”

“…Although gp130-stimulation leads to a transient SHP-2 phosphorylation in A375 cells (Figure 5a), SHP-2 activation cannot be essential for the growth arrest of A375 cells since the chimeras Y767 and Y814 lack tyrosine residue Y759 of gp130 required for SHP-2 activation (Stahl et al, 1995) while still being able to mediate growth arrest ( Figure 4). To investigate the e ect of SHP-2 activation without concomitant STAT activation, transfectants were generated that expressed receptors containing tyrosine module Y759 (Figure 3, lower panel).…”

“…Janus kinases Jak1, Jak2 and Tyk2 associated with the membrane-proximal region of gp130 become activated upon stimulation, thus leading to the tyrosine phosphorylation of cellular substrates, among them the cytoplasmic tail of gp130. The four membranedistal tyrosine residues of gp130 are, when phosphorylated, docking sites for the transcription factors STAT3 and STAT1 Stahl et al, 1995). Subsequently, STATs also are tyrosinephosphorylated, form homo-or heterodimers and translocate to the nucleus where they regulate the transcription of target genes.…”

“…Subsequently, STATs also are tyrosinephosphorylated, form homo-or heterodimers and translocate to the nucleus where they regulate the transcription of target genes. The tyrosine phosphatase SHP-2 also binds to a speci®c phosphotyrosine motif of gp130 (Stahl et al, 1995), thereby possibly forming a link to the Ras/Raf/MAP kinase pathway, also known to be activated by IL-6-type cytokines (Boulton et al, 1994;Kumar et al, 1994). Activation of the SHP-2 phosphatase may further lead to downregulation of the signal (Kim et al, 1998;Symes et al, 1997).…”

STAT activation by the PDGF receptor requires juxtamembrane phosphorylation sites but not Src tyrosine kinase activation

“…Upon cytokine receptor oligomerization, JAKs phosphorylate the receptor molecules on tyrosine. This allows the receptor to bind STATs through their SH2 domains (Heim et al, 1995;Stahl et al, 1995). STATs are then phosphorylated by JAKs on a conserved tyrosine residue, which drives the subsequent events of STAT release, dimerization and nuclear translocation (Briscoe et al, 1996).…”