The Shp-2 Tyrosine Phosphatase Has Opposite Effects in Mediating the Activation of Extracellular Signal-regulated and c-Jun NH2-terminal Mitogen-activated Protein Kinases*

Shp-2 is a widely expressed cytoplasmic tyrosine phosphatase with two SH2 domains. A targeted mutant allele of theShp-2 gene with a deletion of 65 amino acids in the NH2-terminal SH2 domain was created that leads to embryonic lethality at mid-gestation in homozygous mutant mice. To define the Shp-2 function in cell signaling, we have established mutant fibroblast cell lines, and have examined the effect of the Shp-2 mutation on extracellular signal-regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK) mitogen-activated protein (MAP) kinase pathways. Insulin-like growth factor (IGF)-I-induced ERK activation was completely abolished, while ERK activity upon platelet-derived growth factor and epidermal growth factor stimulation was significantly reduced and shortened in mutant cells. Stimulation of ERK by phorbol 12-myristate 13-acetate was not affected in mutant cells, but the phorbol 12-myristate 13-acetate-induced ERK activity decayed much faster compared with that in wild-type cells. In contrast, JNK activation upon heat shock was significantly enhanced in Shp-2 mutant cells. Based on these results, we conclude that Shp-2 plays differential positive regulatory roles in various mitogenic signaling pathways leading to ERK activation, and that Shp-2 is a negative effector in JNK activation by cellular stress. This is the first evidence that a tyrosine phosphatase has opposite effects in mediating the activation of ERK and JNK MAP kinases.

• Publication year

  1998

• Venue

  Journal of Biological Chemistry

• Publication date

  1998-02-27

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.273.9.4904PMID 9478933
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• Heat shock-induced JNK activation was enhanced in Shp-2 mutant cells, supporting an opposite regulatory role for Shp-2 in the JNK pathway compared with ERK signaling.

  Confidence 0.97

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• PMA-triggered ERK activation was initially preserved in mutant cells, but the response decayed faster than in wild-type cells.

  Confidence 0.92

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• ERK activation after PDGF or EGF stimulation was reduced and shortened in Shp-2 mutant cells.

  Confidence 0.95

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• IGF-I-induced ERK activation was completely abolished in Shp-2 mutant fibroblasts.

  Confidence 0.98

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review

• egf stimulation

  stimulus, growth factor

  Stimulation of cells with epidermal growth factor as a mitogenic input tested for ERK activation.

  Aliases: epidermal growth factor, EGF

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• erk map kinase pathway

  signaling pathway

  The extracellular signal-regulated kinase signaling cascade measured here by stimulus-induced ERK activation.

  Aliases: ERK pathway, extracellular signal-regulated kinase pathway

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• heat shock

  stress condition

  A cellular stress condition used here to trigger JNK activation.

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• igf-i stimulation

  stimulus, growth factor

  Stimulation of cells with insulin-like growth factor I as a mitogenic input tested for ERK activation.

  Aliases: insulin-like growth factor I, IGF-I

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• jnk map kinase pathway

  signaling pathway

  The c-Jun NH2-terminal kinase signaling cascade measured here by JNK activation after cellular stress.

  Aliases: JNK pathway, c-Jun NH2-terminal kinase pathway

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• nh2-terminal sh2 domain deletion mutant

  genetic variant, protein variant

  A targeted Shp-2 mutant allele carrying a deletion of 65 amino acids in the NH2-terminal SH2 domain.

  Aliases: 65-amino-acid deletion mutant, targeted mutant allele

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• pdgf stimulation

  stimulus, growth factor

  Stimulation of cells with platelet-derived growth factor as a mitogenic input tested for ERK activation.

  Aliases: platelet-derived growth factor, PDGF

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• pma stimulation

  stimulus, chemical

  Treatment with phorbol 12-myristate 13-acetate used here as a direct activator of ERK signaling.

  Aliases: phorbol 12-myristate 13-acetate, PMA

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review
• shp-2 tyrosine phosphatase

  protein, enzyme

  A widely expressed cytoplasmic protein tyrosine phosphatase with two SH2 domains studied here in mutant fibroblasts.

  Aliases: Shp-2

  박진우 (dztg5apj7m) extraction뀨 (7c402c1b98) reviewAK (4715169a40) reviewB (s683577b42) reviewKiller Whale (322360f1c1) reviewq (76h6bfydm6) review

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