The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase

Berto, Gaia; Camera, Paola; Fusco, Carlo; Imarisio, Sara; Ambrogio, Chiara; Chiarle, Roberto; Silengo, Lorenzo; Cunto, Ferdinando Di

doi:10.1242/jcs.000703

Cited by 58 publications

(72 citation statements)

References 39 publications

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“…Both enzymes are activated by rhoA in other tissues (Zhang et al, 2003;Shandala et al, 2004;Berto et al, 2007;Del Re et al, 2007;Hilgers et al, 2007;Peters and Michel, 2007). Increased rhoA expression and activity consistently correlates with increased ROCK1 expression and decreased CRIK expression ( Figure 5C, top).…”

Section: Overexpression Of Obscurin's Rhogef Domain In Adult Skeletalmentioning

confidence: 86%

“…Here, we have shown that the increased expression and activation of rhoA by obscurin's rhoGEF domain increases ROCK1 expression and decreases CRIK expression. ROCK1 activity in striated muscle is associated with hypertrophy and myoblast fusion (Maekawa et al, 1999;Liu et al, 2003;Nishiyama et al, 2004;Castellani et al, 2006;Peters and Michel, 2007), whereas CRIK activity is associated with cytokinesis and Golgi organization (Camera et al, 2003(Camera et al, , 2008Shandala et al, 2004;Berto et al, 2007). RhoA signaling through ROCK1 is a well-characterized pathway that is up-regulated in cardiac hypertrophy, and is responsible for many of the associated morphological changes (Molkentin and Dorn, 2001;Ahuja et al, 2007;Peters and Michel, 2007).…”

Section: Downstream Signalingmentioning

confidence: 99%

“…RhoA elicits its effects through activation of kinases, including rho-kinase (ROCK) and citron kinase (CRIK), as well as through interaction with scaffolding proteins, including rhotekin and diaphanous, and through transcriptional activation of genes containing a serum response element (SRE) in their promoter (Sahai et al, 1998;Wei et al, 1998;Lin et al, 2002;Carson et al, 2003;Shandala et al, 2004;Ahuja et al, 2007). RhoA-CRIK signaling mediates cytokinesis and Golgi organization via changes in the actin cytoskeleton in both muscle and nerve (Camera et al, 2003;Shandala et al, 2004;Ahuja et al, 2007;Berto et al, 2007). RhoA-ROCK1 signaling regulates myoblast fusion as well as muscle hypertrophy, primarily by regulating the nuclear localization of SRF (Wei et al, 1998;Sotiropoulos et al, 1999;Lin et al, 2002;Liu et al, 2003;Li et al, 2005;Castellani et al, 2006;Charrasse et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

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The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Activates RhoA Signaling in Skeletal Muscle

Ford-Speelman

Roche

Bowman

et al. 2009

MBoC

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Obscurin is a large (ϳ800-kDa), modular protein of striated muscle that concentrates around the M-bands and Z-disks of each sarcomere, where it is well positioned to sense contractile activity. Obscurin contains several signaling domains, including a rho-guanine nucleotide exchange factor (rhoGEF) domain and tandem pleckstrin homology domain, consistent with a role in rho signaling in muscle. We investigated the ability of obscurin's rhoGEF domain to interact with and activate small GTPases. Using a combination of in vitro and in vivo approaches, we found that the rhoGEF domain of obscurin binds selectively to rhoA, and that rhoA colocalizes with obscurin at the M-band in skeletal muscle. Other small GTPases, including rac1 and cdc42, neither associate with the rhoGEF domain of obscurin nor concentrate at the level of the M-bands. Furthermore, overexpression of the rhoGEF domain of obscurin in adult skeletal muscle selectively increases rhoA expression and activity in this tissue. Overexpression of obscurin's rhoGEF domain and its effects on rhoA alter the expression of rho kinase and citron kinase, both of which can be activated by rhoA in other tissues. Injuries to rodent hindlimb muscles caused by large-strain lengthening contractions increases rhoA activity and displaces it from the M-bands to Z-disks, similar to the effects of overexpression of obscurin's rhoGEF domain. Our results suggest that obscurin's rhoGEF domain signals at least in part by inducing rhoA expression and activation, and altering the expression of downstream kinases in vitro and in vivo. INTRODUCTIONThe three largest proteins of the sarcomere, titin, nebulin, and obscurin, are critical for the assembly of myofibrils and the structural integrity of the sarcomere. The organization of actin and myosin in the mature myofibril is regulated by nebulin and titin, respectively, but the functions of obscurin, the most recently discovered of the three, are still poorly understood. An orthologue of Unc89 (Benian et al., 1996;Sutter et al., 2004), obscurin was first identified in mammals as a ligand of titin. Like titin, it is a multidomain protein (Young et al., 2001) composed largely of immunoglobulinlike (Ig) domains, which, with two fibronectin-like III (FnIII) domains, comprise its N-terminal and central regions. In the A isoform of obscurin, the C-terminal region of obscurin contains a calmodulin-binding (IQ) motif, followed by several Ig domains, a Src homology (SH) 3 domain, a rhoguanine nucleotide exchange factor (rhoGEF) domain, and tandem pleckstrin homology (PH) domain, two more Ig domains, and some nonmodular sequence. The nonmodular region at the extreme carboxy terminus includes several putative phosphorylation sites for extracellular signal-regulated kinase (ERK) kinases, as well as a binding site for a small, integral membrane form of ankyrin that concentrates in the network sarcoplasmic reticulum (nSR) (Young et al., 2001;Russell et al., 2002;Bagnato et al., 2003; KontrogianniKonstantopoulos et al., 2003;Borzok et al., 2007). This ...

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Section: Overexpression Of Obscurin's Rhogef Domain In Adult Skeletalmentioning

confidence: 86%

Section: Downstream Signalingmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Activates RhoA Signaling in Skeletal Muscle

Ford-Speelman

Roche

Bowman

et al. 2009

MBoC

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“…Citron kinase is also required for neurogenesis LoTurco et al 2003;Ackman et al 2007). In a Down syndrome mouse model, citron kinase is responsible for inhibiting neurite extension (Berto et al 2007). Interestingly, this citron-kinase-mediated neurite inhibition is through a direct interaction with tetratricopeptide repeat protein TTC3, a Drosophila ortholog of dTPR2, which suppresses polyglutamine toxicity in a fly Huntington's disease model (KazemiEsfarjani and Benzer 2000; Berto et al 2007).…”

mentioning

confidence: 99%

Drosophila sticky/citron kinase Is a Regulator of Cell-Cycle Progression, Genetically Interacts With Argonaute 1 and Modulates Epigenetic Gene Silencing

2008

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The sticky/citron kinase protein is a conserved regulator of cell-cycle progression from invertebrates to humans. While this kinase is essential for completion of cytokinesis, sticky/citron kinase phenotypes disrupting neurogenesis and cell differentiation suggest additional non-cell-cycle functions. However, it is not known whether these phenotypes are an indirect consequence of sticky mutant cell-cycle defects or whether they define a novel function for this kinase. We have isolated a temperature-sensitive allele of the Drosophila sticky gene and we show that sticky/citron kinase is required for histone H3-K9 methylation, HP1 localization, and heterochromatin-mediated gene silencing. sticky genetically interacts with Argonaute 1 and sticky mutants exhibit context-dependent Su(var) and E(var) activity. These observations indicate that sticky/citron kinase functions to regulate both actin-myosin-mediated cytokinesis and epigenetic gene silencing, possibly linking cell-cycle progression to heterochromatin assembly and inheritance of gene expression states.

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“…In addition, an upregulation of RhoA immunoreactivity occurs in the brains of patients with intractable epilepsy (Yuan et al, 2010). Also, the Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase (Berto et al, 2007).…”

Section: Oncogenesismentioning

confidence: 99%

RHOA (ras homolog gene family, member A)

Manso¹

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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The Down syndrome critical region protein TTC3 inhibits neuronal differentiation via RhoA and Citron kinase

Cited by 58 publications

References 39 publications

The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Activates RhoA Signaling in Skeletal Muscle

The Rho-Guanine Nucleotide Exchange Factor Domain of Obscurin Activates RhoA Signaling in Skeletal Muscle

Drosophila sticky/citron kinase Is a Regulator of Cell-Cycle Progression, Genetically Interacts With Argonaute 1 and Modulates Epigenetic Gene Silencing

RHOA (ras homolog gene family, member A)

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