Protein Kinase A (PKA) Phosphorylation of Shp2 Protein Inhibits Its Phosphatase Activity and Modulates Ligand Specificity

Burmeister, Brian T.; Wang, Li; Gold, Matthew G.; Skidgel, Randal A.; O’Bryan, John P.; Carnegie, Graeme K.

doi:10.1074/jbc.m115.642983

Cited by 19 publications

(14 citation statements)

References 37 publications

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“…On the contrary, it has been shown that PKA directly inhibits RAF1 through either phosphorylation of S43, 233, and 259 or dephosphorylation of S338 distributed throughout RAF1, which leads to inactivation of the HRAS/ RAF1/MEK/ERK pathway (57)(58)(59)(60). Recently, PKA has been shown to inhibit SHP2, which contradicts our data (61,62). Although our results show that PKA positively acts upstream of SHP2 in the CD99CRIII3-mediated activation of the SHP2/HRAS/RAF1/ERK signaling pathway, how PKA activates SHP2 and whether PKA inhibits the function of RAF1 within this pathway remain unclear.…”

Section: Discussioncontrasting

confidence: 56%

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

Lee

Kim

Yoo

et al. 2017

Molecular and Cellular Biology

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The human CD99 protein is a 32-kDa glycosylated transmembrane protein that regulates various cellular responses, including cell adhesion and leukocyte extravasation. We previously reported that CD99 activation suppresses ␤1 integrin activity through dephosphorylation of focal adhesion kinase (FAK) at Y397. We explored a molecular mechanism underlying the suppression of ␤1 integrin activity by CD99 agonists and its relevance to tumor growth in vivo. CD99-Fc fusion proteins or a series of CD99-derived peptides suppressed ␤1 integrin activity by specifically interacting with three conserved motifs of the CD99 extracellular domain. CD99CRIII3, a representative CD99-derived 3-mer peptide, facilitated protein kinase A-SHP2 interaction and subsequent activation of the HRAS/RAF1/MEK/ERK signaling pathway. Subsequently, CD99CRIII3 induced FAK phosphorylation at S910, which led to the recruitment of PTPN12 and PIN1 to FAK, followed by FAK dephosphorylation at Y397. Taken together, these results indicate that CD99-derived agonist ligands inhibit fibronectin-mediated ␤1 integrin activation through the SHP2/ERK/PTPN12/FAK signaling pathway.

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Section: Discussioncontrasting

confidence: 56%

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

Lee

Kim

Yoo

et al. 2017

Molecular and Cellular Biology

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“…In view of the fact that AKAP binds to PKA regulatory subunits such as RIIβ in order to regulate its interactions and its downstream targets, it is more likely support the involvement of PKA in the development of cardiac hypertrophy. Consistent with that finding, PKA under the influence of AKAP-Lbc, an AKAP, phosphorylates the protein tyrosine phosphatase Shp2 (PTPN11) at Thr73 and Ser189, which was found to be contributing to β-AR-induced cardiomyocyte hypertrophy (49). Also, Wang J, et al (30) have shown that the activity and protein level of PKA in HF is significantly increased compared to non-failing hearts.…”

Section: Protein Kinase a (Pka) In Healthy And Failing Heartsupporting

confidence: 56%

Protein Kinase A as a Promising Target for Heart Failure Drug Development

Saad¹,

Elnakish²,

Ahmed

et al. 2018

Archives of Medical Research

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Heart failure (HF) is a clinical syndrome characterized by impaired ability of the heart to fill or eject blood. HF is rather prevalent and it represents the foremost reason of hospitalization in the United States. The costs linked to HF overrun those of all other causes of disabilities, and death in the United States and all over the developed as well as the developing countries which amplify the supreme significance of its prevention. Protein kinase (PK) A plays multiple roles in heart functions including, contraction, metabolism, ion fluxes, and gene transcription. Altered PKA activity is likely to cause the progression to cardiomyopathy and HF. Thus, this review is intended to focus on the roles of PKA and PKA-mediated signal transduction in the healthy heart as well as during the development of HF. Furthermore, the impact of cardiac PKA inhibition/activation will be highlighted to identify PKA as a potential target for the HF drug development.

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“…This result indicates that tyrosine phosphorylation, an important post-translational modification for Shp2, is also critical for the EMT of cancer cells. A possible explanation is that the tyrosine phosphorylation of Shp2 promotes its phosphatase activity [ 48 ]. Alternatively, these modifications may be essential for the Shp2 function in regulating Erk phosphorylation [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

Shp2 Plays a Critical Role in IL-6-Induced EMT in Breast Cancer Cells

Sun

Zhang

Wang

et al. 2017

IJMS

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Accumulative evidence demonstrates that the protein tyrosine phosphatase Shp2 functions as a powerful tumor promoter in many types of cancers. Abnormal expression of Shp2 has been implicated in many human malignancies. Overexpression of Shp2 in cancer tissues is correlated with cancer metastasis, resistance to targeted therapy, and poor prognosis. The well-known function of Shp2 is its positive role in regulating cellular signaling initiated by growth factors and cytokines, including interleukin-6 (IL-6). Several recent studies have shown that Shp2 is required for epithelial-mesenchymal transition (EMT), triggered by growth factors. However, whether Shp2 is involved in IL-6-signaling-promoted breast cancer EMT and progression, remains undefined. In this study, we showed that exogenous and endogenous IL-6 can enhance breast cancer invasion and migration, through the promotion of EMT. IL-6 also induces the activation of Erk1/2 and the phosphorylation of Shp2. Knockdown of Shp2 attenuated the IL-6-induced downregulation of E-cadherin, as well as IL-6-promoted cell migration and invasion. Moreover, by using Shp2 phosphatase mutants, phosphor-tyrosine mimicking, and deficiency mutants, we provided evidence that the phosphatase activity of Shp2 and its tyrosine phosphorylation, are necessary for the IL-6-induced downregulation of E-cadherin and the phosphorylation of Erk1/2. Our findings uncover an important function that links Shp2 to IL-6-promoted breast cancer progression.

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Protein Kinase A (PKA) Phosphorylation of Shp2 Protein Inhibits Its Phosphatase Activity and Modulates Ligand Specificity

Cited by 19 publications

References 37 publications

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

CD99-Derived Agonist Ligands Inhibit Fibronectin-Induced Activation of β1 Integrin through the Protein Kinase A/SHP2/Extracellular Signal-Regulated Kinase/PTPN12/Focal Adhesion Kinase Signaling Pathway

Protein Kinase A as a Promising Target for Heart Failure Drug Development

Shp2 Plays a Critical Role in IL-6-Induced EMT in Breast Cancer Cells

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