Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

Chaudhary, Fauzia; Lucito, Robert; Tonks, Nicholas K.

doi:10.1042/bj20140573

Cited by 16 publications

(22 citation statements)

References 65 publications

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“…MTSS1 is a multidomain, scaffold protein that normally regulates cytoskeletal dynamics and actin polymerization of the cell [21] , [59] . As a multidomain protein, MTSS1 contains a WH2 [WASP (Wiskott-Aldrich syndrome protein) homology 2] domain and an IMD [IRSp53 (insulin receptor substrate protein of 53 kDa) and MIM homology] domain to help develop the cytoskeletal interactions necessary to promote cellular adhesion [59] .…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, MTSS1 has also been shown to have affinity for protein phosphatases, such as PTPδ and PTPN11, in a range of different cancer subtypes [19] , [20] . The center of the MTSS1 protein is rich in proline, serine, and threonine residues [21] . These residues, all containing hydroxyl groups, interact and bind with these phosphatases, which then may provide a functional link between the MTSS1 protein and signal transduction pathways that prevent an invasive state from arising.…”

Section: Introductionmentioning

confidence: 99%

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PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

et al. 2018

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Pancreatic ductal adenocarcinoma (PDAC) presents at metastatic stage in over 50% of patients. With a survival rate of just 2.7% for patients presenting with distant disease, it is imperative to uncover novel mechanisms capable of suppressing metastasis in PDAC. Previously, we reported that the loss of metastasis suppressor protein 1 (MTSS1) in PDAC cells results in significant increase in cellular migration and invasion. Conversely, we also found that overexpressing MTSS1 in metastatic PDAC cell lines corresponds with not only decreased metastatic phenotype, but also greater overall survival. While it is known that MTSS1 is downregulated in late-stage PDAC, the mechanism behind that loss has not yet been elucidated. Here, we build off our previous findings to present a novel regulatory mechanism for the stabilization of MTSS1 via the tumor suppressor protein phosphatase and tensin homolog (PTEN). We show that PTEN loss in PDAC cells results in a decrease in MTSS1 expression and increased metastatic potential. Additionally, we demonstrate that PTEN forms a complex with MTSS1 in order to stabilize and protect it from proteasomal degradation. Finally, we show that the inflammatory tumor microenvironment, which makes up over 90% of PDAC tumor bulk, is capable of downregulating PTEN expression through secretion of miRNA-23b, potentially uncovering a novel extrinsic mechanism of MTSS1 regulation. Collectively, these data offer new insight into the role and regulation of MTSS1in suppressing tumor cell invasion and migration and help shed light as to what molecular mechanisms could be leading to early cell dissemination in PDAC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

et al. 2018

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“…52–54 Importantly, recent studies have defined an MTSS1-Src-CTTN inhibitory axis involving the Src receptor protein tyrosine phosphatase (PTP), PTPδ. 55 By suppressing cellular levels of PTPδ, MTSS1 inhibits the dephosphorylation and activation of Src, thereby blocking the activation of CTTN. Here we show that loss of Akt2 in CRC cells results in robust induction of MTSS1 both in vitro and in vivo , and that the accumulated protein is able to engage the MTSS1-Src-cortactin inhibitory axis, as indicated by decreased levels of pSrc (Y416) and pCTTN (Y421).…”

Section: Discussionmentioning

confidence: 99%

“…This leads to inhibition of Src, likely through downregulation of PTPδ, a phosphatase that removes the inhibitory phosphorylation of Src at Y527, 55 allowing activation of the kinase via autophosphorylation at Y416. 55 Src is known to have multiple substrates that can affect cell proliferation, survival, adhesion and migration; 66,67 thus multiple metastasis-related processes would be affected by Src inhibition. A major target is CTTN, which requires phosphorylation by Src at Y421 to regulate actin dynamics and promote cell motility, invasion and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis

et al. 2017

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Survival signaling is critical for the metastatic program of cancer cells. The current study investigated the role of Akt survival proteins in colorectal cancer (CRC) metastasis and explored potential mechanisms of Akt-mediated metastasis regulation. Using an orthotopic implantation model in mice, which uniquely recapitulates the entire multistep process of CRC metastasis, combined with an inducible system of short hairpin RNA-mediated Akt isoform knockdown in human CRC cells, our studies confirm a role of Akt2 in CRC cell dissemination to distant organs in vivo. Akt2 deficiency profoundly inhibited the development of liver lesions in mice, whereas Akt1 had no effect under the experimental conditions used in the study. Array analysis of human metastatic genes identified the scaffolding protein metastasis suppressor 1 (MTSS1) as a novel Akt2-regulated gene. Inducible loss of Akt2 in CRC cells robustly upregulated MTSS1 at the messenger RNA and protein level, and the accumulated protein was functionally active as shown by its ability to engage an MTSS1-Src-cortactin inhibitory axis. MTSS1 expression led to a marked reduction in levels of functional cortacin (pcortactin Y421), an actin nucleation-promoting factor that has a crucial role in cancer cell invasion and metastasis. MTSS1 was also shown to mediate suppressive effects of Akt2 deficiency on CRC cell viability, survival, migration and actin polymerization in vitro. The relevance of these findings to human CRC is supported by analysis of The Cancer Genome Atlas (TCGA) and NCBI GEO data sets, which demonstrated inverse changes in expression of Akt2 and MTSS1 during CRC progression. Taken together, the data identify MTSS1 as a new Akt2-regulated gene, and point to suppression of MTSS1 as a key step in the metastasis-promoting effects of Akt2 in CRC cells.

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“…Phosphatases are critical for normal cell signaling, and alterations to phosphatase expression or localization and phosphatase mutation arise in numerous diseases and can alter response to therapy [2,3]. Interestingly, elevated phosphatase activity can sometimes promote, rather than antagonize, pathogenic signaling.…”

Section: Protein Phosphatasesmentioning

confidence: 99%

Cell signaling regulation by protein phosphorylation: a multivariate, heterogeneous, and context-dependent process

Day

Sosale

Lazzara

2016

Current Opinion in Biotechnology

105

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Proper spatiotemporal regulation of protein phosphorylation in cells and tissues is required for normal development and homeostasis, but aberrant protein phosphorylation regulation leads to various diseases. The study of signaling regulation by protein phosphorylation is complicated in part by the sheer scope of the kinome and phosphoproteome, dependence of signaling protein functionality on cellular localization, and the complex multivariate relationships that exist between protein phosphorylation dynamics and the cellular phenotypes they control. Additional complexities arise from the ability of microenvironmental factors to influence phosphorylation-dependent signaling and from the tendency for some signaling processes to occur heterogeneously among cells. These considerations should be taken into account when measuring cell signaling regulation by protein phosphorylation.

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Missing-in-Metastasis regulates cell motility and invasion via PTPδ-mediated changes in SRC activity

Cited by 16 publications

References 65 publications

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

PTEN-Dependent Stabilization of MTSS1 Inhibits Metastatic Phenotype in Pancreatic Ductal Adenocarcinoma

Role of Akt2 in regulation of metastasis suppressor 1 expression and colorectal cancer metastasis

Cell signaling regulation by protein phosphorylation: a multivariate, heterogeneous, and context-dependent process

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