Proper positioning of the cleavage furrow requires α-actinin to regulate the specification of different populations of microtubules

Srinivas, Vinayaka; Murata‐Hori, Maki

doi:10.1242/jcs.107409

Cited by 4 publications

(1 citation statement)

References 31 publications

(38 reference statements)

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“…We need to take into account evidence that not only the two filament systems interact with each other in vivo (72) but also that α-actinin specifically plays an integral role in the cooperative regulation of microtubular and actin cytoskeleton dynamics (73–75). In addition, as both RACK1 and α-actinin have been implicated in costimulatory and/or adhesion signaling which closely follows the TCR triggering event (71, 76, 77), it would be not entirely surprising that their TCR-induced complex formation would integrate signals from multiple receptors, including TCR/CD4, CD28, and integrins, and orchestrate the complex cooperative microtubular and F-actin cytoskeleton rearrangement.…”

Section: Discussionmentioning

confidence: 99%

TCR Triggering Induces the Formation of Lck–RACK1–Actinin-1 Multiprotein Network Affecting Lck Redistribution

et al. 2016

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The initiation of T-cell signaling is critically dependent on the function of the member of Src family tyrosine kinases, Lck. Upon T-cell antigen receptor (TCR) triggering, Lck kinase activity induces the nucleation of signal-transducing hubs that regulate the formation of complex signaling network and cytoskeletal rearrangement. In addition, the delivery of Lck function requires rapid and targeted membrane redistribution, but the mechanism underpinning this process is largely unknown. To gain insight into this process, we considered previously described proteins that could assist in this process via their capacity to interact with kinases and regulate their intracellular translocations. An adaptor protein, receptor for activated C kinase 1 (RACK1), was chosen as a viable option, and its capacity to bind Lck and aid the process of activation-induced redistribution of Lck was assessed. Our microscopic observation showed that T-cell activation induces a rapid, concomitant, and transient co-redistribution of Lck and RACK1 into the forming immunological synapse. Consistent with this observation, the formation of transient RACK1–Lck complexes were detectable in primary CD4+ T-cells with their maximum levels peaking 10 s after TCR–CD4 co-aggregation. Moreover, RACK1 preferentially binds to a pool of kinase active pY394Lck, which co-purifies with high molecular weight cellular fractions. The formation of RACK1–Lck complexes depends on functional SH2 and SH3 domains of Lck and includes several other signaling and cytoskeletal elements that transiently bind the complex. Notably, the F-actin-crosslinking protein, α-actinin-1, binds to RACK1 only in the presence of kinase active Lck suggesting that the formation of RACK1–pY394Lck–α-actinin-1 complex serves as a signal module coupling actin cytoskeleton bundling with productive TCR/CD4 triggering. In addition, the treatment of CD4+ T-cells with nocodazole, which disrupts the microtubular network, also blocked the formation of RACK1–Lck complexes. Importantly, activation-induced Lck redistribution was diminished in primary CD4+ T-cells by an adenoviral-mediated knockdown of RACK1. These results demonstrate that in T cells, RACK1, as an essential component of the multiprotein complex which upon TCR engagement, links the binding of kinase active Lck to elements of the cytoskeletal network and affects the subcellular redistribution of Lck.

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Section: Discussionmentioning

confidence: 99%

TCR Triggering Induces the Formation of Lck–RACK1–Actinin-1 Multiprotein Network Affecting Lck Redistribution

et al. 2016

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p90 ribosomal S6 kinase 1 (RSK1) isoenzyme specifically regulates cytokinesis progression

Nam

Lee

Jang

et al. 2014

Cellular Signalling

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The non-muscle functions of actinins: an update

Foley

Young

2014

Biochemical Journal

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α-Actinins are a major class of actin filament cross-linking proteins expressed in virtually all cells. In muscle, actinins cross-link thin filaments from adjacent sarcomeres. In non-muscle cells, different actinin isoforms play analogous roles in cross-linking actin filaments and anchoring them to structures such as cell-cell and cell-matrix junctions. Although actinins have long been known to play roles in cytokinesis, cell adhesion and cell migration, recent studies have provided further mechanistic insights into these functions. Roles for actinins in synaptic plasticity and membrane trafficking events have emerged more recently, as has a 'non-canonical' function for actinins in transcriptional regulation in the nucleus. In the present paper we review recent advances in our understanding of these diverse cell biological functions of actinins in non-muscle cells, as well as their roles in cancer and in genetic disorders affecting platelet and kidney physiology. We also make two proposals with regard to the actinin nomenclature. First, we argue that naming actinin isoforms according to their expression patterns is problematic and we suggest a more precise nomenclature system. Secondly, we suggest that the α in α-actinin is superfluous and can be omitted.

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Proper positioning of the cleavage furrow requires α-actinin to regulate the specification of different populations of microtubules

Cited by 4 publications

References 31 publications

TCR Triggering Induces the Formation of Lck–RACK1–Actinin-1 Multiprotein Network Affecting Lck Redistribution

TCR Triggering Induces the Formation of Lck–RACK1–Actinin-1 Multiprotein Network Affecting Lck Redistribution

p90 ribosomal S6 kinase 1 (RSK1) isoenzyme specifically regulates cytokinesis progression

The non-muscle functions of actinins: an update

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