Identification of a Novel, Tissue-Specific Calpainhtra-3;a Human Homologue of theCaenorhabditis elegansSex Determination Gene

Mugita, Norifumi; Kimura, Yuri; Ogawa, Michio; Saya, Hideyuki; Nakao, Mitsuyoshi

doi:10.1006/bbrc.1997.7571

Cited by 37 publications

(22 citation statements)

References 20 publications

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“…CAPN6 shares common structural characteristics with other calpain family members, such as Capn5 and C. elegans TRA-3 (Barnes and Hodgkin, 1996;Dear et al, 1997;Mugita et al, 1997), constituting an evolutionarily conserved subfamily. Although CAPN5 and TRA-3 are proteolytic calpains, it might be interesting to examine whether this non-proteolytic activity is also shared by these calpains and whether it is conserved across species.…”

Section: Discussionmentioning

confidence: 99%

“…Approximately one-half of calpains share a common four-domain structure comprising domains I to IV: domain II is a cysteine protease domain; domain III is related to the C2 domain, a Ca not likely to be a proteolytic enzyme (Dear et al, 1997). In CAPN6, as well as Capn5, the C-terminal structure is defined as a diverged C2-domain (also called domain T) instead of as domain IV, on the basis of similarity to Caenorhabditis elegans TRA-3, a nematode sex determination factor (Barnes and Hodgkin, 1996;Dear et al, 1997;Goll et al, 2003;Mugita et al, 1997). Recently, we have demonstrated that CAPN6 can bind to microtubules, mainly through domain III, and induce microtubule stabilization through nonproteolytic activity (Tonami et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1

Tonami

Kurihara

Arima

et al. 2011

Journal of Cell Science

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2+-and phospholipid-binding module; and domain IV is characterized by the presence of multiple EF-hand motifs in some members, including the classical calpains (m-and -calpains) (Croall and Ersfeld, 2007;Goll et al., 2003). Among the 14 or 15 members of the calpain family in mammals, calpain-6 (CAPN6) is unique in that it lacks the active-site catalytic cysteine residue and is therefore SummaryCrosstalk between microtubules and actin filaments is crucial for various cellular functions, including cell migration, spreading and cytokinesis. The Rac1 GTPase plays a key role in such crosstalk at the leading edge of migrating cells in order to promote lamellipodial formation. However, the mechanism underlying the link between microtubules and Rac1 activation remains unclear. Here, we show that calpain-6 (CAPN6), a non-proteolytic calpain with microtubule-binding and -stabilizing activity, might participate in this crosstalk. Small interfering RNA (siRNA)-induced knockdown of Capn6 in NIH 3T3 cells resulted in Rac1 activation, which promoted cell migration, spreading and lamellipodial protrusion. This increase in Rac1 activity was abolished by knockdown of the Rho guanine nucleotide exchange factor GEF-H1 (officially known as Arhgef2). CAPN6 and GEF-H1 colocalized with microtubules and also interacted with each other through specific domains. Upon knockdown of Capn6, GEF-H1 was shown to translocate from microtubules to the lamellipodial region and to interact with Rac1. By contrast, RhoA activity was decreased upon knockdown of Capn6, although low levels of active RhoA or the presence of RhoA molecules appeared to be required for the Capn6-knockdown-induced Rac1 activation. We suggest that CAPN6 acts as a potential regulator of Rac1 activity, through a mechanism involving interaction with GEF-H1, to control lamellipodial formation and cell motility.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1

Tonami

Kurihara

Arima

et al. 2011

Journal of Cell Science

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“…Surprisingly, a single nucleotide polymorphism (SNP) in tra-3 was reported to be related to the temperature-size rule of wild-type nematodes [74]. Mammals have two orthologues of TRA-3, calpain-5/hTRA-3, and calpain-6, whose amino acid sequences are more than 30% identical to that of TRA-3 [29,108,171]. The C-terminal domain was once called the "T domain", is conserved in all three molecules, and has weak similarity to the Ca 2+ -binding C2-domain.…”

Section: The Palb Subfamilymentioning

confidence: 99%

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

2010

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Abstract:Calpains are intracellular Ca 2+ -dependent cysteine proteases (Clan CA, family C02, EC 3.4.22.17) found in almost all eukaryotes and some bacteria. Calpains display limited proteolytic activity at neutral pH, proteolysing substrates to transform and modulate their structures and activities, and are therefore called "modulator proteases". The human genome has 15 genes that encode a calpain-like protease domain, generating diverse calpain homologues that possess combinations of several functional domains such as Ca 2+ -binding domains and Zn-finger domains. The importance of the physiological roles of calpains is reflected in the fact that particular defects in calpain functionality cause a variety of deficiencies in many different organisms, including lethality, muscular dystrophies, lissencephaly, and tumorigenesis. In this review, the unique characteristics of this distinctive protease superfamily are introduced in terms of genetically modified animals, some of which are animal models of calpain deficiency diseases.

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“…This conclusion was made after the detection of atypical T-domain-containing calpains 5 and 6 in vertebrates (Mugita et al, 1997;Dear et al, 1997), homologous to C. elegans TRA-3, probably, their direct ancestor. Since plants and fungi lack TRA-3 homologues and typical EF-hand Ca 2+ -binding calpains (Wolfe et al, 1989;Mewes et al, 1997) it was supposed that the the first round of duplication that led to the separation of TRA-3 and typical calpains occurred earlier than the divergence of the lines of protostomatic and deuterostomatic animals.…”

Section: Gene Duplicationmentioning

confidence: 93%

“…PBH domain, or MIT (microtubule-interacting and transport) domain, is usually found in AAA-ATPases and some proteins lacking ATPase domains, such as PalB from Aspergillus (Mugita et al, 1997); it is responsible for the association with microtubules and intracellular traffic of molecules. (Ersfeld et al, 2005).…”

Section: Other Structural and Functional Modulesmentioning

confidence: 99%

Molecular Evolution Within Protease Family C2, or Calpains

Лысенко¹,

Немова²

2012

Protein Engineering

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Identification of a Novel, Tissue-Specific Calpainhtra-3;a Human Homologue of theCaenorhabditis elegansSex Determination Gene

Cited by 37 publications

References 20 publications

Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1

Calpain-6, a microtubule-stabilizing protein, regulates Rac1 activity and cell motility through interaction with GEF-H1

Expanding Members and Roles of the Calpain Superfamily and Their Genetically Modified Animals

Molecular Evolution Within Protease Family C2, or Calpains

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