Agonist-induced translocation of protein kinase C (PKC) isozymes is mediated by receptors for the activated form of the kinase, shuttling it from one intracellular site to another and enhancing its catalytic activity. It is however unknown whether the receptors themselves are anchored to certain intracellular structures prior to their engagement with PKC. We show here sequestering of receptor for activated C kinase 1 (RACK1) to the cytoskeleton through the cytoskeletal linker protein plectin during the initial stages of cell adhesion. We found that upon PKC activation, RACK1 was released from the cytoskeleton and transferred to the detergent-soluble cell compartment, where it formed an inducible triple complex with one of the PKC isozymes, PKCdelta, and with plectin. In plectin-deficient cells the cytoskeleton-associated RACK1 fraction was reduced, and the protein was found predominantly at sites to which it normally translocated upon PKC activation. Concomitantly, dislocation of PKCdelta and elevated enzymatic activity were observed in these cells. PKCdelta was also more rapidly degraded, likely due to its overactivation. We propose a previously unrecognized function of plectin as cytoskeletal regulator of PKC signaling, and possibly other signaling events, through sequestration of the scaffolding protein RACK1.
"Plectin is an intermediate filament (IF)-associated linker protein that also functions to regulate actin dynamics and serves as a scaffold for signaling proteins. RACK1-Plectin interactions are particularly important in recruiting and maintaining kinases at the IF cytoskeleton, regulating keratin architecture, adhesion and migration in epithelial cells [32,33]. The RACK1-Keratin interaction is also important in regulation of PKCalpha activity and stabilisation of desmosomes to control intercellular adhesion . "
[Show abstract][Hide abstract] ABSTRACT: This perspective summarises the first and long overdue RACK1 meeting held at the University of Limerick, Ireland, May 2013 in which RACK1's role in the immune system, the heart and the brain were discussed and its contribution to disease states such as cancer, cardiac hypertrophy and addiction were described.RACK1 is a scaffolding protein and a member of the WD repeat family of proteins. These proteins have a unique architectural assembly that facilitates protein anchoring and the stabilisation of protein activity. A large body of evidence is accumulating which is helping to define the versatile role of RACK1 in assembling and dismantling complex signaling pathways from the cell membrane to the nucleus in health and disease. In this commentary, we first provide a historical perspective on RACK1. We also address many of the pertinent and topical questions about this protein such as its role in transcription, epigenetics and translation, its cytoskeletal contribution and the merits of targeting RACK1 in disease.
Cell Communication and Signaling 08/2013; 11(1):53. DOI:10.1186/1478-811X-11-53 · 3.38 Impact Factor
"In myofibers, the contractile apparatus is suspended in a network of desmin filaments linked to the nuclear envelope and the sarcoplasmatic reticulum via plectin isoform 1 (P1), to sarcolemmal costameres and Z-disks via P1f and P1d, respectively, and to mitochondria via P1b [7-9]. Apart from functioning as structural reinforcement and organizing elements of the cytoskeleton, plectin isoforms play also an important role as scaffolding platforms for signaling proteins involved in cell metabolism, stress response, and motility [10-13]. "
[Show abstract][Hide abstract] ABSTRACT: Background:
Duchenne muscular dystrophy (DMD) is one of the most frequent forms of muscular disorders. It is caused by the absence of dystrophin, a core component of the sarcolemma-associated junctional complex that links the cytoskeleton to the extracellular matrix. We showed previously that plectin 1f (P1f), one of the major muscle-expressed isoforms of the cytoskeletal linker protein plectin, accumulates at the sarcolemma of DMD patients as well as of mdx mice, a widely studied animal model for DMD.Based on plectin's dual role as structural protein and scaffolding platform for signaling molecules, we speculated that the dystrophic phenotype observed after loss of dystrophin was caused, at least to some extent, by excess plectin. Thus, we hypothesized that elimination of plectin expression in mdx skeletal muscle, while probably resulting in an overall more severe phenotype, may lead to a partial phenotype rescue. In particular, we wanted to assess whether excess sarcolemmal plectin contributes to the dysregulation of sugar metabolism in mdx myofibers.
We generated plectin/dystrophin double deficient (dKO) mice by breeding mdx with conditional striated muscle-restricted plectin knockout (cKO) mice. The phenotype of these mice was comparatively analyzed with that of mdx, cKO, and wild-type mice, focusing on structural integrity and dysregulation of glucose metabolism.
We show that the accumulation of plectin at the sarcolemma of mdx muscle fibers hardly compensated for their loss of structural integrity. Instead, it led to an additional metabolic deficit by impairing glucose uptake. While dKO mice suffered from an overall more severe form of muscular dystrophy compared to mdx or plectin-deficient mice, sarcolemmal integrity as well as glucose uptake of their myofibers were restored to normal levels upon ablation of plectin. Furthermore, microtubule (MT) networks in intact dKO myofibers, including subsarcolemmal areas, were found to be more robust than those in mdx mice. Finally, myotubes differentiated from P1f-overexpressing myoblasts showed an impairment of glucose transporter 4 translocation and a destabilization of MT networks.
Based on these results we propose that sarcolemma-associated plectin acts as an antagonist of MT network formation in myofibers, thereby hindering vesicle-mediated (MT-dependent) transport of glucose transporter 4. This novel role of plectin throws a bridge between extra-sarcomeric cytoarchitecture and metabolism of muscle fibers. Our study thus provides new insights into pathomechanisms of plectinopathies and muscular dystrophies in general.
"Lately, it has become clear that plectin, in addition to structurally reinforcing the cytoskeleton, acts as a scaffold for molecules and proteins involved in signaling, by positioning them at specific sites within the cells. Examples are the signaling molecule phosphatidylinositol-4,5-bisphosphate (PIP2; involved in the interaction of plectin with actin; Andrä et al. 1998), the nonreceptor tyrosine kinase Fer (requires plectin to turn down its autophosphorylation; Lunter and Wiche 2002), the receptor for activated C kinase 1 (RACK1; when bound to plectin downregulates PKC signaling during the initial stages of cell adhesion; Osmanagic-Myers and Wiche 2004), the γ-subunit of AMP-activated protein kinase (AMPK; associates with Z-disk-bound plectin in differentiated myofibers; Gregor et al. 2006), components of the MAP kinase Erk 1/2 signaling pathway (required for controlled cell migration; Osmanagic-Myers et al. 2006), the chemokine receptor CXCR4 (plays an important role in stromal-derived factor-1 signaling and trafficking, and in HIV-1 infection; Ding et al. 2008), the RON receptor (a member of the Met proto-oncogen family frequently overexpressed in pancreatic cancer; Yu et al. 2012), and the NR3a subunit of the glutamate receptor (Eriksson et al. 2007). "
[Show abstract][Hide abstract] ABSTRACT: Plectin is a large, 500-kDa, intermediate filament (IF)-associated protein. It acts as a cytoskeletal crosslinker and signaling scaffold, affecting mechanical as well as dynamic properties of the cytoskeleton. As a member of the plakin family of cytolinker proteins, plectin has a multidomain structure that is responsible for its vast binding portfolio. It not only binds to all types of IFs, actin filaments and microtubules, but also to transmembrane receptors, proteins of the subplasma membrane protein skeleton, components of the nuclear envelope, and several kinases with known roles in migration, proliferation, and energy metabolism of cells. Due to alternative splicing, plectin is expressed as various isoforms with differing N-terminal heads that dictate their differential subcellular targeting. Through specific interactions with other proteins at their target sites and their ability to bind to all types of IFs, plectin molecules provide strategically located IF anchorage sites within the cytoplasm of cells. In this review, we will present an overview of the structural features and functional properties of plectin and discuss recent progress in defining the role of its isoforms in stress-prone tissues and the implicated diseases, with focus on skin, skeletal muscle, and Schwann cells of peripheral nerve.
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