Specific recruitment of SH-PTP1 to the erythropoietin receptor causes inactivation of JAK2 and termination of proliferative signals

Abstract

The binding of erythropoietin (EPO) to its receptor (EPO-R) activates the protein tyrosine kinase JAK2. The mechanism of JAK2 inactivation has been unclear. We show that the hematopoietic protein tyrosine phosphatase SH-PTP1 (also called HCP and PTP1C) associates via its SH2 domains with the tyrosine-phosphorylated EPO-R. In vitro binding studies suggest that Y429 in the cytoplasmic domain of the EPO-R is the binding site for SH-PTP1. Mutant EPO-Rs lacking Y429 are unable to bind SH-PTP1; cells expressing such mutants are hypersensitive to EPO and display prolonged EPO-induced autophosphorylation of JAK2. Our results suggest that activation of SH-PTP1 by binding to the EPO-R plays a major role in terminating proliferative signals.

Association of biliary glycoprotein with protein tyrosine phosphatase SHP-1 in malignant colon epithelial cells

“…Other cell surface receptors bind to SHP-1 in hemopoietic cells (Yi et al, 1993a;Klinmuller et al, 1995;Pani et al, 1995;Burshtyn et al, 1996). Binding of SHP-1 to the ITIM sequence in all these cell surface proteins terminates signalling with profound e ects on cellular proliferation.…”

“…Moreover, in contrast to ITAMs, only one tyrosine of Bgp (Tyr 488 ) was convincingly shown to undergo phosphorylation in cells treated with insulin or with the protein tyrosine phosphatase inhibitor vanadate . Recently, several hematopoietic cell surface receptors, such as the erythropoietin receptor (Klinmuller et al, 1995), the IL-3 receptor, Kit (Yi et al, 1993a,b), FcgRIIB1, the natural killer receptor p58 and B cell antigen receptor (D'Ambrosio et al, 1995;Pani et al, 1995;Burshtyn et al, 1996) have been shown to contain a so-called Immunoreceptor Tyrosine-based Inhibition Motif (ITIM) (D'Ambrosio et al, 1995;Burshtyn et al, 1996). This motif is shorter than that of the ITAMs (Figure 1c) and encompasses a single phosphorylated tyrosine residue followed at position +2 relative to the tyrosine by an obligate leucine.…”

Regulation of theLeishmania-induced innate inflammatory response by the protein tyrosine phosphatase SHP-1

“…In a subsequent study [11], we demonstrated that this pV-mediated protection against leishmaniasis was in part due to an increased production of nitric oxide and pro-inflammatory molecules (such as IL-6, IL-1b, MCP-1/CCL2 and MIP-2/CXCL1), accompanied by increased leukocyte recruitment. Furthermore, we showed that the PTP Src homology 2 domain phosphotyrosine phosphatase 1 (SHP-1), recognized as a negative regulator of numerous phosphotyrosine-dependent signaling pathways in hematopoietic cells [12][13][14][15][16][17], is specifically induced by Leishmania infection and involved in the deactivation of the IFN-c-induced JAK2-dependent signaling pathway [6].…”

Induction of erythroid differentiation by inhibition of Ras/ERK pathway in a Friend murine leukemia cell line

“…Stimulation of EPOR by EPO induces tyrosine phosphorylation of EPOR as well as numerous cytoplasmic proteins, including a receptor-associated protein tyrosine kinase Jak2 (Witthuhn et al, 1993b), phosphatidylinositol-3-kinase (PI3K) (Damen et al, 1993), protein tyrosine phosphatases SHP-1 (Klingmuller et al, 1995) and SHP-2 (Klingmuller 1997;Sharlow et al, 1997), and adapter proteins SHC and Grb2 (Miura et al, 1994;Damen et al, 1993a;He et al, 1995). Transient activation of Jak/ STAT pathway as well as Ras/MAP kinase (MAPK) pathways after EPO-stimulation has been documented (Miura et al, 1994;Sawyer and Penta, 1996;Quelle et al, 1996;Torti et al, 1992;Todokoro et al, 1994;Tilbrook et al, 1996;Gobert et al, 1995;Nagata et al, 1997).…”