Haploinsufficiency of c-Met in <i>cd44</i><sup>−/−</sup> Mice Identifies a Collaboration of CD44 and c-Met In Vivo

Matzke, Alexandra; Sargsyan, Vardanush; Holtmann, Bettina; Aramuni, Gayane; Asan, Esther; Sendtner, Michael; Pace, Giuseppina; Howells, Norma; Zhang, Weiqi; Ponta, Helmut; Orian-Rousseau, Véronique

doi:10.1128/mcb.01355-07

Cited by 54 publications

(36 citation statements)

References 45 publications

(56 reference statements)

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“…We have recently published genetic evidence for such a substitution. 42 Meanwhile, we have also identified a substituting molecule for CD44v6 in CD44 null mice (V.O., V.O.-R., unpublished results, January 2007) confirming further our hypothesis.…”

Section: Discussionsupporting

confidence: 76%

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Tremmel

Matzke

Albrecht

et al. 2009

Blood

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144

128

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IntroductionAngiogenesis is a complex process that leads to the formation of new blood vessels from existing ones. During embryogenesis, angiogenesis complements vasculogenesis, the production of new blood vessels from hematopoietic precursors. In the adult organism, angiogenesis takes place under normal conditions during the female reproductive cycle or under pathologic conditions, such as in tumor growth and wound healing. Secretion of angiogenic factors from the tumor mass induces the formation of blood vessels, which feed cancer cells with oxygen and nutrients. These vessels will eventually be used as a route for the spreading of metastases. 1 Several angiogenic factors have been described, including vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), transforming growth factor-␣ (TGF-␣), TGF-␤, hepatocyte growth factor (HGF), tumor necrosis factor, angiogenin, interleukin-8, and the angiopoietins. 2 The most prominent angiogenic factor is VEGF-A, a member of the VEGF family of growth factors also including placental growth factor and VEGF-B, -C, -D, and -E. 3 VEGFs bind to 3 related members of the VEGFR family, VEGFR-1, -2, and -3. The importance of VEGFs and their receptors is demonstrated by the phenotypes of the respective knockout mice. Indeed, Vegf-A and Vegfr-2 knockout mice show a failure in vasculature formation and die during embryogenesis, whereas Vegfr-1-deficient mice die of an overgrowth of blood vessels. 3 Fighting angiogenesis has become an attractive aim of cancer therapy. Indeed, targeting angiogenesis rather than directly addressing the tumor cells has the advantage that the same reagents can be applied to many different types of tumors. In addition, because of the low turnover rate of endothelial cells (ECs), they are less susceptible to become resistant to chemotherapy. 4 Several anti-VEGF treatment regimens already exist that can be combined with chemotherapy or radiotherapy. These treatments make use of VEGF inhibitors, such as antibodies against VEGF (bevacizumab), several small molecules inhibiting VEGFR-2 signaling, as well as soluble VEGF receptors that compete with the endogenous receptor for binding to VEGF. 5 However, because all these treatments have a relatively modest benefit for most cancer patients, there is still plenty of room for improvement.HGF is another potent angiogenic factor: the expression of HGF and its receptor c-Met correlates with tumor vascularization, 6 the production of VEGF in a variety of cells and tissues is induced by HGF, 7 and HGF can potentiate the activity of VEGF. [8][9][10] Furthermore, HGF leads to mobilization of endothelial progenitor cells, 11 and the expression of a soluble c-Met receptor (decoy Met) impairs tumor angiogenesis. 12 We have previously shown that HGF depends on a CD44 exon v6 containing isoform for the activation of c-Met on epithelial cells. 13 CD44 isoforms containing the variant exon v6 have been shown to be metastatic determinants. 14 The role of CD44v6 in metastasis results most probably from its coop...

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Section: Discussionsupporting

confidence: 76%

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Tremmel

Matzke

Albrecht

et al. 2009

Blood

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144

128

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“…Met, the receptor for the hepatocyte growth factor (HGF), is overexpressed in 20% to 30% of breast cancers, is associated with poor clinical outcome (68,69), and of importance, requires CD44v6 to become fully activated. CD44v6-specific antibodies have been shown to block Met activation in many different cancer cell lines and primary cells, and loss of CD44 in mice correlates with c-Met haploinsufficiency (70,71). Furthermore, CD44v6-ERM interaction is required for activation of c-Met and subsequent downstream activation of the Ras-SOS signaling cascade (72).…”

Section: Cd44 As a Coreceptormentioning

confidence: 99%

Understanding the Dual Nature of CD44 in Breast Cancer Progression

Louderbough

Schroeder

2011

Molecular Cancer Research

236

181

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CD44 has been the subject of extensive research for more than 3 decades because of its role in breast cancer, in addition to many physiological processes, but interestingly, conflicting data implicate CD44 in both tumor suppression and tumor promotion. CD44 has been shown to promote protumorigenic signaling and advance the metastatic cascade. On the other hand, CD44 has been shown to suppress growth and metastasis. Histopathological studies of human breast cancer have correlated CD44 expression with both favorable and unfavorable clinical outcomes. In recent years, CD44 has garnered significant attention because of its utility as a stem cell marker and has surfaced as a potential therapeutic target, necessitating a greater understanding of CD44 in breast cancer. In this review, we attempt to unify the literature implicating CD44 in both tumor promotion and suppression, and explain its dualistic nature. Mol Cancer Res; 9(12); 1573-86. Ó2011 AACR.

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“…Recently, CD44 mRNA has been detected in neurons in the striatum, extended amygdala and certain hypothalamic, cortical and hippocampal regions of the forebrain (Glezer et al, 2009). Moreover, it has been found in the central respiratory control system within the brain stem (Matzke et al, 2007) and granule neurons in the adult cerebellum (Naruse et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, CD44 was suggested to act as a co-receptor for receptor tyrosine kinases and serve as a site for signaling molecule assembly (Sherman et al, 2000;Orian-Rousseau et al, 2002;Matzke et al, 2007;Gorlewicz et al, 2009). Recently, CD44 in sensory neurons has been described to inhibit plasma membrane Ca 2+ adenosine triphosphatase (PMCA) through the activation of Src family kinases (SFKs, Lck, Fyn;Ghosh et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, CD44 in sensory neurons has been described to inhibit plasma membrane Ca 2+ adenosine triphosphatase (PMCA) through the activation of Src family kinases (SFKs, Lck, Fyn;Ghosh et al, 2011). The lack of CD44 in pre-Bötzinger complex interneurons within the brain stem was also shown to reduce glutamatergic synaptic excitation in vivo (Matzke et al, 2007). In conclusion, although the amount of data on neuronal CD44 function is increasing, our understanding of its function is far from being comprehensive.…”

Section: Introductionmentioning

confidence: 99%

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CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi

Skupien¹,

Konopka²,

Trzaskoma³

et al. 2014

Development

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The acquisition of proper dendrite morphology is a crucial aspect of neuronal development towards the formation of a functional network. The role of the extracellular matrix and its cellular receptors in this process has remained enigmatic. We report that the CD44 adhesion molecule, the main hyaluronan receptor, is localized in dendrites and plays a crucial inhibitory role in dendritic tree arborization in vitro and in vivo. This novel function is exerted by the activation of Src tyrosine kinase, leading to the alteration of Golgi morphology. The mechanism operates during normal brain development, but its inhibition might have a protective influence on dendritic trees under toxic conditions, during which the silencing of CD44 expression prevents dendritic shortening induced by glutamate exposure. Overall, our results indicate a novel role for CD44 as an essential regulator of dendritic arbor complexity in both health and disease.

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Haploinsufficiency of c-Met in cd44^−/− Mice Identifies a Collaboration of CD44 and c-Met In Vivo

Cited by 54 publications

References 45 publications

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Understanding the Dual Nature of CD44 in Breast Cancer Progression

CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi

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Haploinsufficiency of c-Met in cd44−/− Mice Identifies a Collaboration of CD44 and c-Met In Vivo

Cited by 54 publications

References 45 publications

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis

Understanding the Dual Nature of CD44 in Breast Cancer Progression

CD44 regulates dendrite morphogenesis through Src tyrosine kinase-dependent positioning of the Golgi

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Product

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Haploinsufficiency of c-Met in cd44^−/− Mice Identifies a Collaboration of CD44 and c-Met In Vivo