Signaling Through the Hematopoietic Cytokine Receptors

Abstract

Hematopoiesis is regulated through the interaction of a variety of growth factors with specific receptors of the cytokine receptor superfamily. Although lacking catalytic domains, all the receptors couple ligand binding to the rapid induction of protein tyrosine phosphorylation. This is mediated through a novel family of protein tyrosine kinases termed the Janus kinases (Jaks) which associate with the receptors and are activated following ligand binding. Depending upon the cytokine/receptor system, one or more of the four known Jaks (Jak1, Jak2, Jak3, Tyk2) is/are involved. The activated Jaks phosphorylate both themselves and the receptor subunits, creating docking sites for SH2-containing proteins including SHC, which couples receptor engagement to activation of the ras pathway, and HCP, a protein tyrosine phosphatase which negatively affects the response. In addition, the Jaks phosphorylate one or more of a family of signal transducers and activators of transcription (Stats). Phosphorylation of Stats induces their nuclear translocation and DNA-binding activity. Activation of Stats is independent of activation of the ras pathway and represents a novel signaling pathway correlated with mitogenesis.

The Prolactin Receptor and Severely Truncated Erythropoietin Receptors Support Differentiation of Erythroid Progenitors

“…All of the signaling proteins known to be activated by the EpoR, including JAK2, STAT5, SH-PTP1, Grb2, and Ras, are also activated by other cytokine receptors (6,7). Here we show that the unique outcome of EpoR signaling is not due to any unique signals it may generate, but instead is encoded in the cellular environment of erythroid progenitors.…”

Constitutive membrane association potentiates activation of Bruton tyrosine kinase

“…Autophosphorylation of receptor tyrosine kinases creates docking sites to which cytoplasmic signaling proteins bind either directly (Kazlauskas et al, 1989) or via adapter molecules such as Grb2 (Downward, 1994). Signaling through receptors without intrinsic enzymatic activity relies on the activity of constitutively and/or inducibly bound kinases (Ihle et al, 1995;Chan et al, 1994;Cambier et al, 1994). Some nonreceptor tyrosine kinases (NRTKs) also communicate with the plasma membrane and elicit their function independent of cell surface receptors (Resh, 1994).…”

The fibroblast growth factor receptor FGFR-4 acts as a ligand dependent modulator of erythroid cell proliferation

“…for the TGFa and SCF receptors and members of the Jak family (Hayman et al, 1993;Beug et al, 1995;Ihle et al, 1995;Steinlein et al, 1995;Broudy, 1997;Wessely et al, 1997). By using a PCRbased strategy and targeting the conserved kinase encoding region we have attempted (i) to monitor tyrosine kinase gene expression in erythroid cells when cells di erentiate and (ii) to isolate and identify tyrosine kinases that have so far not been implicated in erythroid cell development, and also (iii) to discover new members of the tyrosine kinase family with a potential function in erythroid cells.…”

“…c-kit, IGFR and Jak1 expression was e ectively downregulated in both di erentiating SCF and TGFa progenitors, albeit with di erent kinetics. Jak1 is of particular interest since Jak proteins provide a link between cytokine receptors without intrinsic tyrosine kinase activity and protein substrates, such as the STAT transcription factors, that are tyrosine phosphorylated upon receptor activation and induce speci®c changes in gene expression (Ihle et al, 1995). Interestingly, it has been reported that EGFR and c-kit activate STAT factors in hematopoietic cells (Mellitzer et al, 1996;DeBerry et al, 1997).…”

“…In other instances non-receptor tyrosine kinases, like members of the Janus kinase (Jak) family, conduct the signals originating from cytokine receptors that lack intrinsic tyrosine kinase activity. In both cases, however, receptor and non-receptor tyrosine kinases elicit their speci®c e ects by phosphorylating intracellular target proteins which ultimately induce changes in gene expression (Ullrich and Schlessinger, 1990;Schlessinger and Ullrich, 1992;Ihle et al, 1995;Pawson and Scott, 1997). Most signi®cantly, mutant versions of receptor and non-receptor tyrosine kinases may aberrantly alter normal growth control mechanisms and like in leukemias lead to a massive and uncontrolled outgrowth of largely immature hematopoietic cells that cause the disease (Sawyers et al, 1991).…”