Protein-tyrosine Phosphatase-α and Src Functionally Link Focal Adhesions to the Endoplasmic Reticulum to Mediate Interleukin-1-induced Ca2+ Signaling

Wang, Qin; Rajshankar, Dhaarmini; Branch, Donald R.; Siminovitch, Katherine A.; Abreu, Maria Teresa Herrera; Downey, Gregory P.; McCulloch, Christopher A.

doi:10.1074/jbc.m808828200

Cited by 24 publications

(29 citation statements)

References 76 publications

(68 reference statements)

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“…Src and Fyn) via dephosphorylation of an inhibitory C-terminal tyrosine residue (22)(23)(24)(25)(26)(27). We have also shown that through its interactions with Src, PTP␣ controls IL-1 induced phosphorylation of the inositol 1,4,5-phosphate receptor and consequently, Ca 2ϩ release (28). Further, PTP␣ regulates formation of focal adhesions in response to mechanical force, strengthens connections between integrins and the cytoskeleton, and modulates cytoskeletal reorganization in response to integrin ligation (26,27).…”

mentioning

confidence: 88%

“…Previously, we have reported that interactions between PTP␣ and the Ca 2ϩ release channel IP 3 R1, required the membrane proximal domain (D1) of PTP␣ (28). In contrast, the membrane distal domain has been implicated in interactions between PTP␣ and other receptor phosphatases (39).…”

Section: Ptps In Il-1 Signaling-il-1mentioning

confidence: 99%

“…We pursued this idea by examining another PTP as a test of the specificity of IL-1-induced ERK activation and MMP3 release. PTP␣ was studied because of its central role in IL-1 signaling through focal adhesions (28). Human gingival fibroblasts were transfected with control siRNA (green fluorescent protein) or siRNA specific for PTP␣.…”

Section: Ptps In Il-1 Signaling-il-1mentioning

confidence: 99%

“…Although the individual roles of SHP-2 and PTP␣ in focal adhesion-mediated IL-1 signaling have been partially characterized independently of each of these PTPs (12,21,28,29), whether PTP␣ and SHP-2 act cooperatively to regulate IL-1 signaling is not known. Consequently we examined the functional importance of the catalytic activity of PTP␣ in influencing the interactions between SHP-2 and PTP␣, as well as IL-1-induced signaling that leads to ERK activation and MMP release.…”

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confidence: 99%

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Importance of Protein-tyrosine Phosphatase-α Catalytic Domains for Interactions with SHP-2 and Interleukin-1-induced Matrix Metalloproteinase-3 Expression

Wang

Rajshankar

Laschinger

et al. 2010

Journal of Biological Chemistry

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Interleukin-1 (IL-1) induces extracellular matrix degradation as a result of increased expression of matrix metalloproteinases (MMPs).Reversible phosphorylation of proteins on tyrosine residues is a pivotal, post-translational modification in many signal transduction pathways. The extent of these modifications is determined by the balance between the activities of proteintyrosine kinases and phosphatases (1, 2). Whereas proteintyrosine kinases are thought to regulate the amplitude of responses to extracellular signals, protein-tyrosine phosphatases (PTPs) 2 may determine the rate and duration of these responses (3). For IL-1 signaling in adherent cells, tyrosine phosphorylation of focal adhesion proteins such as the focal adhesion kinase is a critical, rate-limiting process (4). Tyrosine phosphorylated proteins, such as focal adhesion kinase, paxillin, and Src family kinases, which are enriched in focal adhesions (5), influence the assembly, maturation, and disassembly of these adhesive structures (6 -9) and also impact signaling through focal adhesions (10). The dynamic and reversible nature of tyrosine phosphorylation of focal adhesion proteins suggests an important role for protein-tyrosine kinases and PTPs in focal adhesion-dependent signaling (11). There are numerous PTPs in focal adhesions, and, in particular, SHP-2 is recruited to focal adhesions upon integrin engagement (12-14). In the absence of SHP-2, the number of focal adhesions and actin stress fibers increases, which is associated with diminished spreading and motility (15, 16). Expression of a dominant-negative SHP-2 enhances the formation of focal adhesions and stress fibers (17). The dynamics of focal adhesion assembly and IL-1-induced signaling pathways, including Ca 2ϩ release and ERK phosphorylation, are dependent on phosphorylation of Tyr 542 of 18,19), which can in turn affect the phosphatase activity of SHP-2 (20).We recently reported that another PTP, namely PTP␣, plays a prominent role in the regulation of focal adhesions during cell adhesion, spreading, and motility (21). PTP␣ is a receptor-like PTP that can activate Src family kinases (e.g. Src and Fyn) via dephosphorylation of an inhibitory C-terminal tyrosine residue (22)(23)(24)(25)(26)(27). We have also shown that through its interactions with Src, PTP␣ controls IL-1 induced phosphorylation of the inositol 1,4,5-phosphate receptor and consequently, Ca 2ϩ release (28). Further, PTP␣ regulates formation of focal adhesions in response to mechanical force, strengthens connections between integrins and the cytoskeleton, and modulates cytoskeletal reorganization in response to integrin ligation (26,27). In the absence of PTP␣, fibroblasts demonstrated reduced spreading, increased numbers of abnormal focal adhesions, decreased tyrosine phosphorylation of focal * This work was supported by grants from the Canadian Institutes of Health Research (MOP 84254; to C. A. M. and G. P. D.). This work was also supported in part by National Institutes of Health Grant HL090669 (to G. P. D.) and funds ...

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confidence: 88%

Section: Ptps In Il-1 Signaling-il-1mentioning

confidence: 99%

Section: Ptps In Il-1 Signaling-il-1mentioning

confidence: 99%

mentioning

confidence: 99%

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Importance of Protein-tyrosine Phosphatase-α Catalytic Domains for Interactions with SHP-2 and Interleukin-1-induced Matrix Metalloproteinase-3 Expression

Wang

Rajshankar

Laschinger

et al. 2010

Journal of Biological Chemistry

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“…Although not completely understood, localization of GRP78 expression to this region may reflect distinct focal points for the recruitment of GRP78 to the cell surface. Thus, it is interesting to note that ER-resident chaperone proteins such as GRP78, calnexin, and calreticulin can associate with focal adhesions to mediate IL-1-induced Ca 2ϩ signaling (56,57).…”

Section: Discussionmentioning

confidence: 99%

Binding of Anti-GRP78 Autoantibodies to Cell Surface GRP78 Increases Tissue Factor Procoagulant Activity via the Release of Calcium from Endoplasmic Reticulum Stores

Al‐Hashimi

Caldwell

Gonzalez-Gronow

et al. 2010

Journal of Biological Chemistry

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The increased risk of venous thromboembolism in cancer patients has been attributed to enhanced tissue factor (TF) procoagulant activity (PCA) on the surface of cancer cells. Recent studies have shown that TF PCA can be modulated by GRP78, an endoplasmic reticulum (ER)-resident molecular chaperone. In this study, we investigated the role of cell surface GRP78 in modulating TF PCA in several human cancer cell lines. Although both GRP78 and TF are present on the cell surface of cancer cells, there was no evidence of a stable interaction between recombinant human GRP78 and TF, nor was there any effect of exogenously added recombinant GRP78 on cell surface TF PCA. Treatment of cells with the ER stress-inducing agent thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca 2؉

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Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

Stanford

Svensson

Sacchetti

et al. 2016

Arthritis & Rheumatology

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Objective During rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) critically promote disease pathogenesis by aggressively invading the joint extracellular matrix. The focal adhesion kinase (FAK) signaling pathway is emerging as a contributor to RA FLS anomalous behavior. The receptor protein tyrosine phosphatase α (RPTPα), encoded by the PTPRA gene, is a key promoter of FAK signaling. Here we investigated whether RPTPα mediates FLS aggressiveness and RA pathogenesis. Methods Through RPTPα knockdown, we assessed FLS gene expression by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay, invasion and migration in transwell assays, survival by Annexin V and propidium iodide staining, adhesion and spreading by immunofluorescence microscopy, and activation of signaling pathways by Western blotting of FLS lysates. Arthritis development was examined in Ptpra−/− mice using the K/BxN serum transfer model. The contribution of radiosensitive and radioresistant cells to disease was evaluated by reciprocal bone-marrow transplantation. Results RPTPα was enriched in the RA synovial lining. RPTPα knockdown impaired RA FLS survival, spreading, migration, invasiveness and responsiveness to platelet-derived growth factor, tumor necrosis factor and interleukin-1 stimulation. These phenotypes correlated with increased phosphorylation of SRC on inhibitory Y527 and decreased phosphorylation of FAK on stimulatory Y397. Treatment of RA FLS with an inhibitor of FAK phenocopied knockdown of RPTPα. Ptpra-deficient mice were protected from arthritis development, which was due to radioresistant cells. Conclusions By regulating phosphorylation of SRC and FAK, RPTPα mediates pro-inflammatory and pro-invasive signaling in RA FLS, correlating with promotion of disease in an FLS-dependent model of RA.

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Protein-tyrosine Phosphatase-α and Src Functionally Link Focal Adhesions to the Endoplasmic Reticulum to Mediate Interleukin-1-induced Ca2+ Signaling

Cited by 24 publications

References 76 publications

Importance of Protein-tyrosine Phosphatase-α Catalytic Domains for Interactions with SHP-2 and Interleukin-1-induced Matrix Metalloproteinase-3 Expression

Importance of Protein-tyrosine Phosphatase-α Catalytic Domains for Interactions with SHP-2 and Interleukin-1-induced Matrix Metalloproteinase-3 Expression

Binding of Anti-GRP78 Autoantibodies to Cell Surface GRP78 Increases Tissue Factor Procoagulant Activity via the Release of Calcium from Endoplasmic Reticulum Stores

Receptor Protein Tyrosine Phosphatase α–Mediated Enhancement of Rheumatoid Synovial Fibroblast Signaling and Promotion of Arthritis in Mice

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