4.7 Article

The phosphatase Shp1 interacts with and dephosphorylates cortactin to inhibit invadopodia function

期刊

CELL COMMUNICATION AND SIGNALING
卷 19, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12964-021-00747-6

关键词

Src homology region 2 domain-containing phosphatase-1 (Shp1); Cortactin; Invadopodia; Glycerophosphoinositols; Phosphoinositides; Cancer

资金

  1. Italian Association for Cancer Research [IG18776]
  2. PRIN [20177XJCHX]
  3. PNR-CNR Aging Program
  4. PRONAT project
  5. SATIN
  6. CIRO POR project 2014-2020
  7. Italian Foundation for Cancer Research (FIRC, Milan, Italy)

向作者/读者索取更多资源

The research demonstrated that Shp1 plays a crucial role in invadopodia formation by promoting the dephosphorylation of cortactin, thereby reducing melanoma cancer cells' ability to degrade the extracellular matrix. Additionally, the study showed that Shp1 can be considered as a regulator of melanoma cell invasiveness and a potential target for antimetastatic drugs. Glycerophosphoinositol was found to facilitate the localization of Shp1 at invadopodia, leading to impaired invadopodia function and decreased tumor dissemination both in vitro and in an in vivo model of melanomas.
Background: Invadopodia are actin-based cell-membrane protrusions associated with the extracellular matrix degradation accompanying cancer invasion. The elucidation of the molecular mechanisms leading to invadopodia formation and activity is central for the prevention of tumor spreading and growth. Protein tyrosine kinases such as Src are known to regulate invadopodia assembly, little is however known on the role of protein tyrosine phosphatases in this process. Among these enzymes, we have selected the tyrosine phosphatase Shp1 to investigate its potential role in invadopodia assembly, due to its involvement in cancer development. Methods: Co-immunoprecipitation and immunofluorescence studies were employed to identify novel substrate/s of Shp1AQ controlling invadopodia activity. The phosphorylation level of cortactin, the Shp1 substrate identified in this study, was assessed by immunoprecipitation, in vitro phosphatase and western blot assays. Short interference RNA and a catalytically-dead mutant of Shp1 expressed in A375MM melanoma cells were used to evaluate the role of the specific Shp1-mediated dephosphorylation of cortactin. The anti-invasive proprieties of glycerophosphoinositol, that directly binds and regulates Shp1, were investigated by extracellular matrix degradation assays and in vivo mouse model of metastasis. Results: The data show that Shp1 was recruited to invadopodia and promoted the dephosphorylation of cortactin at tyrosine 421, leading to an attenuated capacity of melanoma cancer cells to degrade the extracellular matrix. Controls included the use of short interference RNA and catalytically-dead mutant that prevented the dephosphorylation of cortactin and hence the decrease the extracellular matrix degradation by melanoma cells. In addition, the phosphoinositide metabolite glycerophosphoinositol facilitated the localization of Shp1 at invadopodia hence promoting cortactin dephosphorylation. This impaired invadopodia function and tumor dissemination both in vitro and in an in vivo model of melanomas. Conclusion: The main finding here reported is that cortactin is a specific substrate of the tyrosine phosphatase Shp1 and that its phosphorylation/dephosphorylation affects invadopodia formation and, as a consequence, the ability of melanoma cells to invade the extracellular matrix. Shp1 can thus be considered as a regulator of melanoma cell invasiveness and a potential target for antimetastatic drugs.

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