Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice.

Kozlowski, Maya; Mlinarič-Raščan, Irena; Feng, Gen‐Sheng; Shen, Rongkun; Pawson, Tony; Siminovitch, Katherine A.

doi:10.1084/jem.178.6.2157

Cited by 233 publications

(156 citation statements)

References 25 publications

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“…To specifically ascertain the biologic relevance of SHP-1 to the regulation of Src, activity of this PTK was next investigated in unstimulated thymocytes from motheaten (me) and viable motheaten (me v ) mice, animals that express negligible SHP-1 catalytic activity consequent to lossof-function mutations in the SHP-1 gene (30). As is consistent with previous data from our group (33), the results of anti-Src immunoblotting analysis confirmed the presence of Src in thymocytes from both mutant and normal, congenic mice.…”

Section: Resultsmentioning

confidence: 99%

“…The SRC2 rabbit polyclonal anti-Src antibody, which recognizes a similar epitope as clone 28 and was demonstrated in comparative studies to also selectively immunoprecipitate the active form of Src (data not shown), was obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Rabbit polyclonal anti-SHP-1 antibody recognizing the tandem SH2 domains of SHP-1 was generated in our laboratory as described previously (30). Rabbit anti-p56 lck antibody was produced in our laboratory by immunizing rabbits with a bacterial TrpE fusion protein containing amino acids 7-144 of Lck (31).…”

Section: Methodsmentioning

confidence: 99%

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Src Kinase Activity Is Regulated by the SHP-1 Protein-tyrosine Phosphatase

Somani¹,

Bignon²,

Mills³

et al. 1997

Journal of Biological Chemistry

158

125

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Activation of the cellular Src tyrosine kinase depends upon dephosphorylation of the carboxyl-terminal inhibitory tyrosine phosphorylation site. Herein we show that Src isolated from human platelets and Jurkat T cells is preferentially dephosphorylated at its inhibitory phosphotyrosine site by the SHP-1 tyrosine phosphatase. The data also revealed association of Src with SHP-1 in both platelets and lymphocytes and the capacity of Src to phosphorylate SHP-1 and interact with the SHP-1 NH 2 -terminal SH2 domain in vitro. Analysis of Src activity in thymocytes from SHP-1-deficient motheaten and viable motheaten mice revealed this kinase activity to be substantially lower than that detected in wild-type thymocytes, but to be enhanced by in vitro exposure to SHP-1. Similarly, immunoblotting analysis of thymocyte Src expression before and after selective depletion of active Src protein indicated that the proportion of active relative to inactive Src protein is markedly reduced in motheaten compared with wild-type cells. These observations, together with the finding of reduced Src activity in HEY cells expressing a dominant negative form of SHP-1, provide compelling evidence that SHP-1 functions include the positive regulation of Src activation.Both the kinase and transforming activities of the pp60 c-src (Src) protein-tyrosine kinase (PTK) 1 are repressed by phosphorylation of a tyrosine residue within the Src carboxyl terminus (1-5). The negative regulatory effect of this phosphotyrosine (Tyr-530 and Tyr-529 in human and murine Src, respectively) has been ascribed to its association with the Src SH2 domain and consequent SH2, as well as SH3 domain-mediated intramolecular interactions that repress activity of the kinase domain (6 -8). The catalytic activities of the other Src family members are similarly inhibited by phosphorylation of this conserved C-tail tyrosine (9), and activation of each of these PTKs thus depends on dephosphorylation at this site. However, while several lines of evidence implicate the Csk tyrosine kinase (10 -12) as well as Src-mediated autophosphorylation (13) in the phosphorylation of the COOH-terminal regulatory tyrosine, relatively little is known about the mechanisms whereby this inhibitory phosphotyrosine residue is dephosphorylated and Src activation achieved. In contrast to the Src-related Lck and possibly Fyn PTKs, the Src COOH-terminal phosphotyrosine does not appear subject to dephosphorylation by the transmembrane protein-tyrosine phosphatase (PTP), CD45 (14 -16). Moreover, while Src activity has been found to be increased in rodent cell lines overexpressing the receptor-like protein-tyrosine phosphatase, RPTP␣ (17, 18), a direct role for this PTP in dephosphorylating Tyr-529 in vivo has not been established. However, recent data from studies of the SHP-1 tyrosine phosphatase, a cytosolic, dual SH2 domain-containing protein expressed primarily in hemopoietic and epithelial cells (19 -22), have raised the possibility that this PTP plays a role in the dephosphorylation and activation ...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Src Kinase Activity Is Regulated by the SHP-1 Protein-tyrosine Phosphatase

Somani¹,

Bignon²,

Mills³

et al. 1997

Journal of Biological Chemistry

158

125

View full text Add to dashboard Cite

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“…Northern blotting was conducted as described (16). Membranes were incubated with a-32 P ATP-labeled cDNA probes encoding either human SHP1 or 18S probe.…”

Section: Northern Blottingmentioning

confidence: 99%

“…How JNK activation induces inhibitory and antiproliferative signals in IGF-stimulated breast cancer cells remains unknown (13). To understand the antiproliferative activity of JNK in IGF-1-stimulated MCF-7 breast adenocarcinoma cells, we investigated the role of a well-studied SH-2 domaincontaining tyrosine phosphatase SHP1 whose activity has been associated with the termination of mitogenic cascades and signals activated by cytokines and antigens in hematopoietic cells (14)(15)(16)(17)(18)(19).…”

Section: Introductionmentioning

confidence: 99%

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Amin

Kumar

Nilchi

et al. 2011

Molecular Cancer Research

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In this study, we show that proliferation of breast cancer cells is suppressed by IGF-1-activated JNK MAPK pathway. The molecular mechanism by which c-jun-NH,-kinase (JNK) activation induces antiproliferative signals in IGF-1-stimulated breast cancer cells remains unknown. Tyrosine phosphatase SHP1 is known to negatively regulate signal transduction pathways activated by cell surface receptors including IGF-1. Moreover, SHP1 transcript and protein levels are increased in epithelial tumors. Therefore, we hypothesized that IGF-activated JNK induces expression of SHP1 in breast cancer cells. To further clarify the role of SHP1 in tumor growth, we correlated the proliferation rates of breast adenocarcinoma cells with SHP1 expression and JNK activation. We show that proliferation of serum-or IGF-1-stimulated breast adenocarcinoma cells is negatively regulated by SHP1 and show for the first time that IGF-1-activated JNK induces SHP1 expression in MCF-7 cells used as experimental model. In an attempt to understand the mechanism by which serum-or IGF-1-activated JNK induces SHP1 expression resulting in suppression of cell proliferation, we reveal for the first time that in serum-or IGF-1-stimulated breast cancer MCF-7 cells, JNK induces SHP1 expression through the binding of AP-4 and RFX-1 transcription factors to the epithelial tissue-specific SHP1 promoter. Overall, we show for the first time that IGF-1-stimulated proliferation of breast adenocarcinoma cells is negatively regulated by SHP1 through activation of JNK. Mol Cancer Res; 9(8); 1112-25. Ó2011 AACR.

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“…To detect Shp-1 gene mutation, PCR-based genotyping was performed as previously described (38). All animal experiments were conducted according to the guideline of Tokyo Metropolitan Institute for Neuroscience.…”

Section: Micementioning

confidence: 99%

Positive and Negative Regulation of High Affinity IgE Receptor Signaling by Src Homology Region 2 Domain-Containing Phosphatase 1

Nakata

Yoshimaru

Suzuki

et al. 2008

The Journal of Immunology

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Src homology region 2 domain-containing phosphatase 1 (SHP-1), a cytoplasmic protein tyrosine phosphatase, plays an important role for the regulation of signaling from various hematopoietic cell receptors. Although SHP-1 is shown to be a negative signal modulator in mast cells, its precise molecular mechanisms are not well defined. To elucidate how SHP-1 regulates mast cell signaling, we established bone marrow-derived mast cells from SHP-1-deficient motheaten and wild-type mice and analyzed downstream signals induced by cross-linking of high affinity IgE receptor, FcεRI. Upon FcεRI ligation, motheaten-derived bone marrow-derived mast cells showed enhanced tyrosine phosphorylation of Src homology region 2 domain-containing leukocyte protein of 76 kDa (SLP-76) and linker for activation of T cells, activation of mitogen-activated protein kinases and gene transcription and production of cytokine. Because the activity of Syk, responsible for the phosphorylation of SLP-76 and linker for activation of T cells, is comparable irrespective of SHP-1, both molecules might be substrates of SHP-1 in mast cells. Interestingly, the absence of SHP-1 expression disrupted the association between SLP-76 and phospholipase Cγ, which resulted in the decreased phospholipase Cγ phosphorylation, calcium mobilization, and degranulation. Collectively, these results suggest that SHP-1 regulates FcεRI-induced downstream signaling events both negatively and positively by functioning as a protein tyrosine phosphatase and as an adaptor protein contributing to the formation of signaling complex, respectively.

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Expression and catalytic activity of the tyrosine phosphatase PTP1C is severely impaired in motheaten and viable motheaten mice.

Cited by 233 publications

References 25 publications

Src Kinase Activity Is Regulated by the SHP-1 Protein-tyrosine Phosphatase

Src Kinase Activity Is Regulated by the SHP-1 Protein-tyrosine Phosphatase

Breast Cancer Cells Proliferation Is Regulated by Tyrosine Phosphatase SHP1 through c-jun N-Terminal Kinase and Cooperative Induction of RFX-1 and AP-4 Transcription Factors

Positive and Negative Regulation of High Affinity IgE Receptor Signaling by Src Homology Region 2 Domain-Containing Phosphatase 1

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