Enhanced FHL2 and TGF-β1 Expression Is Associated With Invasive Growth and Poor Survival in Malignant Melanomas

Westphal, Philipp; Mauch, Cornelia; Florin, Alexandra; Czerwitzki, Jacqueline; Olligschläger, Nina; Wodtke, Claudia; Schüle, Roland; Büttner, Reinhard; Friedrichs, Nicolaus

doi:10.1309/ajcpxec6cit2txaf

Cited by 12 publications

(13 citation statements)

References 38 publications

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“…In sporadic colon cancer and human melanoma, FHL2 are highly expressed by peritumoral fibroblasts and melanoma cells respectively at the invasion front and are infrequently localized in the nuclear. TGF-β1 co-express with FHL2 in both cases, therefore, is believed to be one of the mediators of FHL2 nuclear translocation (Gullotti et al, 2011; Westphal et al, 2015). Apparently, the pleiotropic functions of FHL2 as an adaptor protein may rely on its subcellular localization when traffic between nucleus and cytoplasm.…”

Section: Resultsmentioning

confidence: 99%

The FHL2 regulation in the transcriptional circuitry of human cancers

Cao

Mok

Cheng

et al. 2015

Gene

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Section: Resultsmentioning

confidence: 99%

The FHL2 regulation in the transcriptional circuitry of human cancers

Cao

Mok

Cheng

et al. 2015

Gene

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“…Exaggerated expression of FHL2 is often associated with tumorigenesis. It is noteworthy that FHL2 might support tumor growth and metastasis, both directly being overexpressed in tumor cells and indirectly when it is overexpressed in tumorassociated stroma cells (2,10,26,85,86). To the contrary, sustained down-regulation of the FHL2 protein supports MMP expression and transition of wounds into chronic forms (30,31,42).…”

Section: Expression Of Fhl2 During Wound Healingmentioning

confidence: 99%

The role of FHL2 in wound healing and inflammation

Wixler

2019

FASEB j.

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The 4‐and‐a‐half LIM domain protein 2 (FHL2) is a multifunctional adaptor protein that can interact with cell surface receptors, cytosolic adaptor and structural proteins, kinases, and nuclear transcription factors. It is involved in numerous functional activities, including the epithelial‐mesenchymal transition, cell proliferation, apoptosis, adhesion, migration, structural stability, and gene expression. Despite this, FHL2‐knockout (KO) mice are viable and fertile with no obvious abnormalities, rather suggesting a high capacity for fine‐tuning adjustment and functional redundancy of FHL2. Indeed, challenging FHL2‐KO cells or mice provided numerous evidences for the great functional significance of FHL2. In recent years, several reviews have been published describing the high capacity of FHL2 to bind diverse proteins as well as the versatile functions of FHL2, emphasizing in particular its role in cardiovascular diseases and carcinogenesis. Here, we view the function of FHL2 from a different perspective. We summarize the published data demonstrating the impact of FHL2 on wound healing and inflammation. FHL2 seems to be involved in numerous steps of these extremely complex and multidirectional but tightly regulated tissue remodeling processes, supporting tissue repair and coordinating inflammation. Deficiency of FHL2 not only slows down ongoing wound healing but also often turns it into a chronic condition.—Wixler, V. The role of FHL2 in wound healing and inflammation. FASEB J. 33, 7799–7809 (2019). http://www.fasebj.org

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“…Interestingly, FHL2 is expressed at low levels in many tissues like breast, placenta, uterus, and the lungs (17,19) and is up-regulated in cancer. For example, FHL2 expression is increased in many cancers including breast (20,21), ovarian (22), prostate (23), lung (24), colon (25), brain (26), and skin cancers (27). In primary breast tumors, patients with high levels of FHL2 have a poorer survival rate (21), suggesting that FHL2 may be involved in cancer progression.…”

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confidence: 99%

Mammalian Actin-binding Protein-1/Hip-55 Interacts with FHL2 and Negatively Regulates Cell Invasion

Boateng

Bennin

Oliveira

et al. 2016

Journal of Biological Chemistry

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Mammalian actin-binding protein-1 (mAbp1) is an adaptor protein that binds actin and modulates scission during endocytosis. Recent studies suggest that mAbp1 impairs cell invasion; however, the mechanism for the inhibitory effects of mAbp1 remain unclear. We performed a yeast two-hybrid screen and identified the adaptor protein, FHL2, as a novel binding partner that interacts with the N-terminal actin depolymerizing factor homology domain (ADFH) domain of mAbp1. Here we report that depletion of mAbp1 or ectopic expression of the ADFH domain of mAbp1 increased Rho GTPase signaling and breast cancer cell invasion. Moreover, cell invasion induced by the ADFH domain of mAbp1 required the expression of FHL2. Taken together, our findings show that mAbp1 and FHL2 are novel binding partners that differentially regulate Rho GTPase signaling and MTLn3 breast cancer cell invasion.Invasive migration of cancer cells is dependent on a dynamic actin cytoskeleton (1). Key regulators of the actin cytoskeleton include actin-binding proteins like cortactin, which have been implicated in invadopodia and podosome formation and invasive cell migration. Mammalian actin-binding protein-1 (mAbp1, 2 Hip-55, DBNL) has significant structural homology to cortactin and binds actin with an N-terminal ADFH domain (2). Both mAbp1 and cortactin have identified roles during endocytosis and vesicle trafficking (3-5), and both proteins localize to lamellipodia, podosomes, and dorsal ruffles (4, 6, 7). However, in contrast to cortactin, mAbp1 impairs podosome formation and invasive migration of Src-transformed fibroblasts (8).To determine how mAbp1 regulates cell invasion, we performed a yeast two-hybrid screen and identified the fourand-a-half LIM domain protein 2 (FHL2) as a novel mAbp1-binding partner that does not interact with cortactin. FHL2 (also known as DRAL or SLIM3) is a LIM domain protein consisting of four-and-a-half LIM domains. Each LIM domain contains two zinc finger loops that mediate proteinprotein interactions. FHL2 interacts with Ͼ50 proteins (9) including integrins and focal adhesion kinase (FAK) (10, 11), actin (12), and the transcription factors estrogen receptor (ER), activator protein-1 (AP-1), and ␤-catenin (13-18). Interestingly, FHL2 is expressed at low levels in many tissues like breast, placenta, uterus, and the lungs (17, 19) and is up-regulated in cancer. For example, FHL2 expression is increased in many cancers including breast (20, 21), ovarian (22), prostate (23), lung (24), colon (25), brain (26), and skin cancers (27). In primary breast tumors, patients with high levels of FHL2 have a poorer survival rate (21), suggesting that FHL2 may be involved in cancer progression. Furthermore, overexpression of FHL2 in MDA-MB-231 human breast cancer cells enhances colony formation in soft agar, whereas knockdown reduces the ability to form colonies (20).Here we report a novel interaction between the N-terminal ADFH domain of mAbp1 and FHL2 that modulates cell invasion. In the yeast, but not the mammalian form, the N terminu...

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Enhanced FHL2 and TGF-β1 Expression Is Associated With Invasive Growth and Poor Survival in Malignant Melanomas

Cited by 12 publications

References 38 publications

The FHL2 regulation in the transcriptional circuitry of human cancers

The FHL2 regulation in the transcriptional circuitry of human cancers

The role of FHL2 in wound healing and inflammation

Mammalian Actin-binding Protein-1/Hip-55 Interacts with FHL2 and Negatively Regulates Cell Invasion

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