5′-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion

Rajadurai, Charles V.; Havrylov, Serhiy; Coelho, Paula P.; Ratcliffe, Colin D.H.; Zaoui, Kossay; Huang, Bruce H.; Monast, Anie; Chughtai, Naila; Sangwan, Veena; Gertler, Frank B.; Siegel, Peter M.; Park, Morag

doi:10.1083/jcb.201501003

Cited by 29 publications

(30 citation statements)

References 56 publications

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“…SHIP2 modulators could also be useful in the treatment of some cancers, e.g., in breast cancer and colorectal cancer in PTEN/INPP4B-deficient cells. Considering the role of SHIP2 in migration and invasion particularly, in some breast cancer cell types (86), or colorectal cancer (51), inhibitors of SHIP2 could be useful as an additional therapy in preventing or controlling cell migration and metastasis by inhibiting PI(3,4)P 2 signaling (40). This could be particularly important in estrogen receptornegative breast cancers, in which SHIP2 phosphatase activity has been suggested to modulate tumorigenicity in vivo (80).…”

Section: Inhibitors Of Pi 5-phosphatasesmentioning

confidence: 99%

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Ramos

Ghosh

Erneux

2019

Journal of Lipid Research

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Phosphoinositides (PIs) are recognized as major signaling molecules in many different functions of eukaryotic cells. PIs can be dephosphorylated by multiple phosphatase activities at the 5-, 4- and 3- positions. Human PI 5-phosphatases belong to a family of 10 members. Except for INPP5A, they all catalyze the dephosphorylation of PI(4,5)P2 and/or PI(3,4,5)P3 at the 5- position. PI 5-phosphatases thus directly control the levels of PI(3,4,5)P3 and also participate in fine-tuning regulatory mechanisms of PI(3,4)P2 and PI(4,5)P2. Second messenger functions have been demonstrated for PI(3,4)P2 in invadopodium maturation and in lamellipodia formation. PI 5-phosphatases can use several substrates on isolated enzymes, and it has been challenging to establish their real substrate in vivo. PI(4,5)P2 has multiple functions in signaling, including interaction with scaffold proteins, ion channels, and cytoskeleton proteins. PI 5-phosphatase isoenzymes have been individually implicated in human diseases, such as the oculocerebrorenal syndrome of Lowe, through mechanisms which include lipid-controlling. Oncogenic and tumor suppressive functions of PI 5-phosphatases have also been reported in different cell contexts. The mechanisms responsible for genetic diseases and for tumor suppressor or oncogenic functions are not fully understood. The regulation of PI 5-phosphatases is thus crucial in understanding cell functions.

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Section: Inhibitors Of Pi 5-phosphatasesmentioning

confidence: 99%

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Ramos

Ghosh

Erneux

2019

Journal of Lipid Research

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“…Notably, miR-205-5p as well as miR-200/141 and 429 were anti-correlated (rho ≤ −0.4) to the EMT-related transcription factors ZEB1 and ZEB2 (Figures 7C and S7C). Other anti-correlated miR-205-5p targets potentially related to EMT included connective tissue growth factor (CTGF), cysteine-rich protein 61 (CYR61) (Lau, 2016; Thakur and Mishra, 2016; Yeger and Perbal, 2016), and the inositol phosphatase INPPL1 (SHIP2), which is involved in extracellular matrix (ECM) degradation and carcinoma invasiveness (Rajadurai et al, 2016). The EMT-related mRNAs ZEB2, CTGF, and CYR61 were observed to cluster together above in a branch of mRNA C1 with LUSC and C6 with HNSC that overlap miRNA C2 and C3 with decreased expression of these miRs (Figure S7A, mRNA track).…”

Section: Resultsmentioning

confidence: 99%

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

Campbell¹,

Yau²,

Bowlby³

et al. 2018

Cell Reports

269

303

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SUMMARY This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the ΔNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T-regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches.

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“…Mena isoforms have been shown to bind and be recruited by PH domain-containing proteins such as Lamellipodin3335, and by SHIP275 which in turn bind to phosphoinositides at the plasma membrane. The localization of the phosphoinositide PI(3,4)P2 to invadopodia has recently been characterized20, and localizes to invadopodia with the similarly diffuse distribution that we observe here for Mena isoforms (Fig.…”

Section: Discussionmentioning

confidence: 99%

MenaINV dysregulates cortactin phosphorylation to promote invadopodium maturation

Weidmann

Surve

Eddy

et al. 2016

Sci Rep

Self Cite

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Invadopodia, actin-based protrusions of invasive carcinoma cells that focally activate extracellular matrix-degrading proteases, are essential for the migration and intravasation of tumor cells during dissemination from the primary tumor. We have previously shown that cortactin phosphorylation at tyrosine residues, in particular tyrosine 421, promotes actin polymerization at newly-forming invadopodia, promoting their maturation to matrix-degrading structures. However, the mechanism by which cells regulate the cortactin tyrosine phosphorylation-dephosphorylation cycle at invadopodia is unknown. Mena, an actin barbed-end capping protein antagonist, is expressed as various splice-isoforms. The MenaINV isoform is upregulated in migratory and invasive sub-populations of breast carcinoma cells, and is involved in tumor cell intravasation. Here we show that forced MenaINV expression increases invadopodium maturation to a far greater extent than equivalent expression of other Mena isoforms. MenaINV is recruited to invadopodium precursors just after their initial assembly at the plasma membrane, and promotes the phosphorylation of cortactin tyrosine 421 at invadopodia. In addition, we show that cortactin phosphorylation at tyrosine 421 is suppressed by the phosphatase PTP1B, and that PTP1B localization to the invadopodium is reduced by MenaINV expression. We conclude that MenaINV promotes invadopodium maturation by inhibiting normal dephosphorylation of cortactin at tyrosine 421 by the phosphatase PTP1B.

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5′-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion

Cited by 29 publications

References 56 publications

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

The impact of phosphoinositide 5-phosphatases on phosphoinositides in cell function and human disease

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

MenaINV dysregulates cortactin phosphorylation to promote invadopodium maturation

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