Role of Transmembrane 4 Superfamily (Tm4sf) Proteins Cd9 and Cd81 in Muscle Cell Fusion and Myotube Maintenance

Tachibana, Isao; Hemler, Martin E.

doi:10.1083/jcb.146.4.893

Cited by 221 publications

(170 citation statements)

References 79 publications

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“…In vitro, ␤ 1 -deficient mpc can establish cell-to-cell adhesion, but they are unable to proceed into myotube formation (Schwander et al, 2003). ␤ 1 integrins may form a complex with the tetraspanin CD9 (Hemler, 2001), a molecule involved in murine mpc fusion and myotube maintenance (Tachibana and Hemler, 1999), and, in this way, play a part in mpc fusion (Schwander et al, 2003). However, fusion defects are rescued when ␤ 1 -deficient and wild-type mpc are mixed, indicating that ␤ 1 integrins have to establish heterophilic interactions with another cell surface receptor, which may belong to ADAMs (Hirsch et al, 1998;Schwander et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Lafuste

Sonnet

Chazaud

et al. 2005

MBoC

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Knowledge on molecular systems involved in myogenic precursor cell (mpc) fusion into myotubes is fragmentary. Previous studies have implicated the a disintegrin and metalloproteinase (ADAM) family in most mammalian cell fusion processes. ADAM12 is likely involved in fusion of murine mpc and human rhabdomyosarcoma cells, but it requires yet unknown molecular partners to launch myogenic cell fusion. ADAM12 was shown able to mediate cell-to-cell attachment through binding ␣ 9 ␤ 1 integrin. We report that normal human mpc express both ADAM12 and ␣ 9 ␤ 1 integrin during their differentiation. Expression of ␣ 9 parallels that of ADAM12 and culminates at time of fusion. ␣ 9 and ADAM12 coimmunoprecipitate and participate to mpc adhesion. Inhibition of ADAM12/␣ 9 ␤ 1 integrin interplay, by either ADAM12 antisense oligonucleotides or blocking antibody to ␣ 9 ␤ 1 , inhibited overall mpc fusion by 47-48%, with combination of both strategies increasing inhibition up to 62%. By contrast with blockade of vascular cell adhesion molecule-1/␣ 4 ␤ 1 , which also reduced fusion, exposure to ADAM12 antisense oligonucleotides or anti-␣ 9 ␤ 1 antibody did not induce detachment of mpc from extracellular matrix, suggesting specific involvement of ADAM12-␣ 9 ␤ 1 interaction in the fusion process. Evaluation of the fusion rate with regard to the size of myotubes showed that both ADAM12 antisense oligonucleotides and ␣ 9 ␤ 1 blockade inhibited more importantly formation of large (>5 nuclei) myotubes than that of small (2-4 nuclei) myotubes. We conclude that both ADAM12 and ␣ 9 ␤ 1 integrin are expressed during postnatal human myogenic differentiation and that their interaction is mainly operative in nascent myotube growth. INTRODUCTIONAdult skeletal muscle regeneration after injury results from activation, proliferation, and fusion of mononucleated myogenic precursor cells (mpc) (Hawke and Garry, 2001). The mpc fusion results from an ordered sequence of events, including clustering and alignment of cells, establishment of close cell-to-cell contacts, and plasma membrane merging (Doberstein et al., 1997;Taylor, 2003). Various membrane proteins have been implicated in myotube formation, including N-and M-cadherins, neural cell adhesion molecule (NCAM), and vascular cell adhesion molecule (VCAM), ␣ 4 ␤ 1 and other integrins, and a disintegrin and metalloproteinases (ADAMs) (Abmayr et al., 2003). ADAMs form a family of Ͼ30 transmembrane glycoproteins with a unique domain organization, including a prodomain, a proteolytic domain (metalloprotease), an adhesion integrin-binding site formed by both disintegrin and cysteine-rich domains, an epidermal growth factor-like domain, a transmembrane domain, and a signaling cytoplasmic tail (Huovila et al., 1996;Primakoff and Myles, 2002;White, 2003). In addition, some ADAMs contain a hydrophobic sequence in a cysteine-rich region that may represent a fusion peptide, suggesting that this subclass of ADAMs might participate to plasma membrane merging (Huovila et al., 1996). Some ADAMs have been implicated i...

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Section: Discussionmentioning

confidence: 99%

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Lafuste

Sonnet

Chazaud

et al. 2005

MBoC

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“…In particular, tetraspanin CD9 and CD81 have been implicated in muscle cell fusion, mononuclear phagocytes and linked to the virus-induced syncitium formation. [15][16][17] ADAMs were initially discovered as proteins involved in fertilization, muscle fusion and organ development. 18,19 In this study, we provide evidence that proteins ADAM10, GTP-binding protein a13, radixin, myosin regulatory light chain and RhoA promote cell fusion in colon cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Cell fusion promotes chemoresistance in metastatic colon carcinoma

et al. 2012

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Chemoresistance is an important concern in the treatment of metastatic colon cancer. It may emerge through selection of clones that are inherently resistant from the outset or through mechanisms acquired during treatment. Cell fusion represents an efficient means of rapid phenotypic evolution that make cells with new properties at a rate exceeding that achievable by random mutagenesis. Here, we first identified a number of proteins involved in cell fusion using a shotgun proteomics approach, then we investigated the role of these proteins namely tetraspanin CD81/CD9, ADAM10, GTP-binding protein a13, radixin, myosin regulatory light chain and RhoA in the regulation of colon cancer cell fusion. We also found a previously unrecognized role of ADAM10, Ga13 and RhoA in promoting cell fusion. Finally, we show that the occurrence of cell fusion in a metastatic model of colon carcinoma causes the appearance of cells resistant to both 5-fluorouracil and oxaliplatin. These findings highlight the importance of cell fusion in cancer progression and raise significant implications for overcoming chemoresistance in metastatic colon cancer.

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“…The role of CD9 and CD81 in myogenesis and muscle regeneration has not been thoroughly investigated. CD9 and CD81 monoclonal antibodies were shown to slightly delay the formation of myotubes by the C2C12 muscle cells, and to trigger apoptotic degeneration of C2C12 myotubes in vitro 27 . In addition, ectopic expression of CD9 in a rhabdomyosarcoma cell line increased syncytia formation 27 .…”

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confidence: 97%

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

et al. 2013

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Skeletal muscle regeneration after injury follows a remarkable sequence of synchronized events. However, the mechanisms regulating the typical organization of the regenerating muscle at different stages remain largely unknown. Here we show that muscle regeneration in mice lacking either CD9 or CD81 is abnormal and characterized by the formation of discrete giant dystrophic myofibres, which form more quickly in the absence of both tetraspanins. We also show that, in myoblasts, these two tetraspanins associate with the immunoglobulin domain molecule CD9P-1 (EWI-F/FPRP), and that grafting of CD9P-1-depleted myoblasts in regenerating muscles also leads to abnormal regeneration. In vitro myotubes lacking CD9P-1 or both CD9 and CD81 fuse with a higher frequency than normal myotubes. Our study unveils a mechanism preventing inappropriate fusion of myotubes that has an important role in the restitution of normal muscle architecture during muscle regeneration.

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Role of Transmembrane 4 Superfamily (Tm4sf) Proteins Cd9 and Cd81 in Muscle Cell Fusion and Myotube Maintenance

Cited by 221 publications

References 79 publications

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

Cell fusion promotes chemoresistance in metastatic colon carcinoma

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

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Role of Transmembrane 4 Superfamily (Tm4sf) Proteins Cd9 and Cd81 in Muscle Cell Fusion and Myotube Maintenance

Cited by 221 publications

References 79 publications

ADAM12 and α9β1Integrin Are Instrumental in Human Myogenic Cell Differentiation

ADAM12 and α9β1Integrin Are Instrumental in Human Myogenic Cell Differentiation

Cell fusion promotes chemoresistance in metastatic colon carcinoma

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

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ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation

ADAM12 and α₉β₁Integrin Are Instrumental in Human Myogenic Cell Differentiation