Ras Oncoprotein Induces CD44 Cleavage through Phosphoinositide 3-OH Kinase and the Rho Family of Small G Proteins

Kawano, Yoshiaki; Okamoto, Isamu; Murakami, Daizo; Itoh, Hiroshi; Yoshida, Masaki; Ueda, Shoichi; Saya, Hideyuki

doi:10.1074/jbc.m002440200

Cited by 66 publications

(54 citation statements)

References 55 publications

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“…HA activates PI3 kinase-AKT pathways leading to cell motility and cell survival-signaling pathways [63]. The active mutant of the p110 subunit of PI3 kinase causes the cleavage of CD44 during cancer cell migration [64]. These findings suggest PI3 kinase activation is closely coupled with HAmediated CD44 signaling.…”

Section: Ha/cd44mentioning

confidence: 63%

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

Bourguignon

2008

Seminars in Cancer Biology

270

279

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Hyaluronan (HA), a major component of the extracellular matrix (ECM), is enriched in many types of tumors. In cancer patients HA concentrations are usually higher in malignant tumors than in corresponding benign or normal tissues, and in some tumor types the level of HA is predictive of malignancy. HA is often bound to CD44 isoforms which are ubiquitous, abundant, and functionally important cell surface receptors. This article reviews the current evidence for HA/CD44-mediated activation of the ankyrin-based cytoskeleton and RhoGTPase signaling during tumor progression. A special focus is placed on the role of HA-mediated CD44 interaction with unique downstream effectors (e.g., the cytoskeletal protein, ankyrin and/or various GTPases (e.g., RhoA, Rac1 and Cdc42)) in coordinating intracellular signaling pathways (e.g., Ca 2+ mobilization, Rho signaling, PI3 kinase-AKT activation, NHE1-mediated cellular acidification, transcriptional upregulation and cytoskeletal function) and generating the concomitant onset of tumor cell activities (e.g., tumor cell adhesion, growth, survival, migration and invasion) and tumor progression. I believe this information will provide valuable new insights into poorly understood aspects of solid tumor malignancy. Furthermore, the new knowledge concerning HA/CD44-mediated oncogenic signaling events will have potentially important clinical utility, and could establish CD44 and its associated signaling molecules as important tumor markers for the early detection and evaluation of oncogenic potential. It could also serve as ground work for the future development of new drug targets to inhibit HA/ CD44-mediated tumor metastasis and cancer progression.

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Section: Ha/cd44mentioning

confidence: 63%

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

Bourguignon

2008

Seminars in Cancer Biology

270

279

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“…Cleavage of CD44 has been suggested to play an important role in tumor cell migration along extracellular matrix components (8,9). Cleavage of the extracellular region is promoted by various pathways, such as those activated by extracellular Ca 2ϩ influx, protein kinase C, Rho family small GTPases, and Rac and Ras oncoproteins (8,9).…”

mentioning

confidence: 99%

Ligand-induced Structural Changes of the CD44 Hyaluronan-binding Domain Revealed by NMR

Takeda

Ogino

Umemoto

et al. 2006

Journal of Biological Chemistry

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CD44, a major cell surface receptor for hyaluronan (HA), contains a functional domain responsible for HA binding at its N terminus (residues 21-178). Accumulating evidence indicates that proteolytic cleavage of CD44 in its extracellular region (residues 21-268) leads to enhanced tumor cell migration and invasion. Hence, understanding the mechanisms underlying the CD44 proteolytic cleavage is important for understanding the mechanism of CD44-mediated tumor progression. Here we present the NMR structure of the HA-binding domain of CD44 in its HA-bound state. The structure is composed of the Link module (residues 32-124) and an extended lobe (residues 21-31 and 125-152). Interestingly, a comparison of its unbound and HA-bound structures revealed that rearrangement of the ␤-strands in the extended lobe (residues 143-148) and disorder of the structure in the following C-terminal region (residues 153-169) occurred upon HA binding, which is consistent with the results of trypsin proteolysis studies of the CD44 HA-binding domain. The order-to-disorder transition of the C-terminal region by HA binding may be involved in the CD44-mediated cell migration.

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“…We previously proposed a proteolysis-model for the regulation of CD44 function ( Figure 1a) (Okamoto et al, 1999a(Okamoto et al, , b, 2001Kawano et al, 2000). CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains.…”

mentioning

confidence: 99%

Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44

et al. 2003

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CD44 is the major adhesion molecule for the extracellular matrix components and is implicated in a wide variety of physiological and pathological processes including the regulation of tumor cell growth and metastasis. Our previous studies have shown that CD44 undergoes sequential proteolytic cleavages in the extracellular and transmembrane domains and the cleavage product derived from CD44 intramembranous cleavage acts as a signal transduction molecule. However, the underlying mechanism of the intramembranous cleavage of CD44 remains to be elucidated. In the present study, we report for the first time that CD44 is a substrate of the presenilin (PS)-dependent c-secretase. We demonstrate that the intramembranous cleavage of CD44 induced by 12-Otetradecanoylphorbol 13-acetate (TPA) treatment or mechanical scraping is blocked by c-secretase inhibitors in U251MG cells and that this cleavage is also inhibited in PS-deficient mouse embryonic fibroblasts. Furthermore, we showed that PS1 is redistributed to ruffling areas of the plasma membrane similarly to CD44 after TPA treatment, supporting our biochemical observation that PS1 is involved in the intramembranous cleavage of CD44. Our present findings suggest important implications for understanding CD44-dependent signal transduction and a potential role of PS/c-secretase activity in the functional regulation of adhesion molecules.

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Ras Oncoprotein Induces CD44 Cleavage through Phosphoinositide 3-OH Kinase and the Rho Family of Small G Proteins

Cited by 66 publications

References 55 publications

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression

Ligand-induced Structural Changes of the CD44 Hyaluronan-binding Domain Revealed by NMR

Presenilin-dependent γ-secretase activity mediates the intramembranous cleavage of CD44

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