Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

Tehrani, Shandiz; Faccio, Roberta; Chandrasekar, Indra; Ross, F. Patrick; Cooper, John A.

doi:10.1091/mbc.e06-03-0187

Cited by 126 publications

(122 citation statements)

References 49 publications

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“…3D, lanes 3 and 4). This observation confirms the previous observations of ours and others that an increase in the phosphorylation of several signaling proteins is necessary for osteoclast bone resorption (6,7,14,18,38).…”

Section: Analysis Of the Phosphoprotein Profile In Osteoclasts Incubasupporting

confidence: 93%

“…Cortactin has been implicated in osteoclast podosome assembly/ disassembly and bone resorption (6,10,62,64). siRNA to cortactin blocked sealing ring formation, but these osteoclasts displayed actin aggregates (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…ABPs assist in stabilizing and rearranging the organization of the actin cytoskeleton in response to external stimuli or during cell migration and adhesion. A few of the ABPs have been identified as having a role in osteoclast function (1)(2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

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Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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The aim of this study is to identify the exact mechanism(s) by which cytoskeletal structures are modulated during bone resorption. In this study, we have shown the possible role of different actin-binding and signaling proteins in the regulation of sealing ring formation. Our analyses have demonstrated a significant increase in cortactin and a corresponding decrease in L-plastin protein levels in osteoclasts subjected to bone resorption for 18 h in the presence of RANKL, M-CSF, and native bone particles. Time-dependent changes in the localization of L-plastin (in actin aggregates) and cortactin (in the sealing ring) suggest that these proteins may be involved in the initial and maturation phases of sealing ring formation, respectively. siRNA to cortactin inhibits this maturation process but not the formation of actin aggregates. Osteoclasts treated as above but with TNF-␣ demonstrated very similar effects as observed with RANKL. Osteoclasts treated with a neutralizing antibody to TNF-␣ displayed podosome-like structures in the entire subsurface and at the periphery of osteoclast. It is possible that TNF-␣ and RANKL-mediated signaling may play a role in the early phase of sealing ring configuration (i.e. either in the disassembly of podosomes or formation of actin aggregates). Furthermore, osteoclasts treated with alendronate or ␣v reduced the formation of the sealing ring but not actin aggregates. The present study demonstrates a novel mechanistic link between L-plastin and cortactin in sealing ring formation. These results suggest that actin aggregates formed by L-plastin independent of integrin signaling function as a core in assembling signaling molecules (integrin ␣v␤3, Src, cortactin, etc.) involved in the maturation process.Osteoclasts, the multinucleated and terminally differentiated giant cells, are involved in bone resorption. The adhesion of osteoclasts to the bone during bone resorption leads to the formation of the clear zone, an actin-rich ring-like adhesion zone circumscribing an area of bone resorption. Formation of a clear zone or sealing zone (also known as the sealing ring) has been considered to be a marker of osteoclast activation and is fundamental to the process of osteoclast bone resorption. Sealing ring formation is mediated by the dynamics of the actin cytoskeleton. Distinct pathways and signaling molecules have been shown to play roles in the organization of the sealing ring during bone resorption. Our previous observations in gelsolin null (Gsn Ϫ/Ϫ ) 2 osteoclasts demonstrated that deficiency of this protein blocks podosome assembly and motility. However, the cells still exhibit sealing ring and matrix resorption (1). Therefore, Gsn Ϫ/Ϫ osteoclasts are capable of resorbing bone, but the resorbed areas are small due to the absence of podosomes and the resulting hypomotile nature of osteoclasts (1). Observations in Gsn Ϫ/Ϫ osteoclasts also suggest that the organization of the sealing ring presumably reflect changes in the role of actinbinding proteins. Spatial configurations of actin fil...

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Section: Analysis Of the Phosphoprotein Profile In Osteoclasts Incubasupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Sadashivaiah

Chellaiah

2010

Journal of Biological Chemistry

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“…Therefore, it is unclear whether potent synergy with cortactin is a general feature of WASP family proteins and if so, whether the mechanism is conserved. Cortactin colocalizes with WASP family proteins such as N-WASP, WASP, and WAVE (Wiskott-Aldrich syndrome protein family verproline-homologous protein) in multiple branched actin networks, including in podosomes (25), at the leading edge of lamellipodia (26), and at sites of endocytosis (27). Determining how branched actin is assembled in each of these structures will require an understanding of how each WASP family protein coordinately regulates Arp2/3 complex with cortactin.…”

mentioning

confidence: 99%

Interactions with Actin Monomers, Actin Filaments, and Arp2/3 Complex Define the Roles of WASP Family Proteins and Cortactin in Coordinately Regulating Branched Actin Networks

Helgeson

Prendergast

Wagner

et al. 2014

Journal of Biological Chemistry

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Background: How cortactin and WASP proteins coordinately regulate branched actin assembly is poorly understood. Results: The Arp2/3 complex-and actin-interacting regions of cortactin and WASP proteins are functionally distinct and tailored to their regulatory roles. Conclusion: Mechanistic distinctions between activators are important in allowing coordinate regulation of branched actin networks. Significance: Understanding mechanistic distinctions between activators is required to understand cellular structures like lamellipodia.

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“…There is a pervasive cytoskeletal-src dependence of proper targeting for the ion transporters of osteoclasts [Zuo et al, 2006: Tehrani et al, 2006: Abu-Amer et al, 1997: Soriano et al, 1991. The actindirected disposition of CLIC protein has also been observed in microvilli of placental cells [Berryman et al, 2004].…”

Section: Bulk Calcium Transport By the Osteoclastmentioning

confidence: 99%

Calcium Signalling and Calcium Transport in Bone Disease

Blair

Schlesinger

Huang

et al.

Subcellular Biochemistry

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Calcium transport and calcium signalling mechanisms in bone cells have, in many cases, been discovered by study of diseases with disordered bone metabolism. Calcium matrix deposition is driven primarily by phosphate production, and disorders in bone deposition include abnormalities in membrane phosphate transport such as in chondrocalcinosis, and defects in phosphate-producing enzymes such as in hypophosphatasia. Matrix removal is driven by acidification, which dissolves the mineral. Disorders in calcium removal from bone matrix by osteoclasts cause osteopetrosis. On the other hand, although bone is central to management of extracellular calcium, bone is not a major calcium sensing organ, although calcium sensing proteins are expressed in both osteoblasts and osteoclasts. Intracellular calcium signals are involved in secondary control including cellular motility and survival, but the relationship of these findings to specific diseases is not clear. Intracellular calcium signals may regulate the balance of cell survival versus proliferation or anabolic functional response as part of signalling cascades that integrate the response to primary signals via cell stretch, estrogen, tyrosine kinase, and tumor necrosis factor receptors Keywords Hypophosphatasia; chondrocalcinosis; osteopetrosis; osteoporosis Although bone is not considered a major calcium sensing organ in humans, the cells of bone tissue control over 99% of the human body's calcium content. The principal calcium sensors that regulate bone calcium uptake and release are in the parathyroid glands. Bone function is also modified by vitamin D and by calcium transport in the kidney and intestine. These indirect mechanisms of controlling bone calcium metabolism are beyond the scope of our considerations here. In spite of processing such massive quantities of the Ca 2+ bone cells use calcium in their homeostatic control processes. The massive movement of calcium is carried out by specialized and regulated transporters. Defects in the transporters cause diseases with affect bone structure or function. Indeed, inborn errors have been very important in defining the calcium transport mechanisms in bone.Additionally, calcium is used by bone forming and bone degrading cells as a secondary mediator of hormone and cytokine action. These actions include roles in intercellular communication within groups of osteoblasts, which are connected by gap junctions [Henriksen et al., 2006]. These osteoblast groups function in a coordinated fashion in bone synthesis and maintenance, and are collectively known as the osteon. Osteoblasts in these groups are connected by gap junctions which are capable of propagating signals in the cell groups, including calcium waves [Xia and Ferrier, 1992]. Calcium is also an important regulator of

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Cortactin Has an Essential and Specific Role in Osteoclast Actin Assembly

Cited by 126 publications

References 49 publications

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Regulation of Sealing Ring Formation by L-plastin and Cortactin in Osteoclasts

Interactions with Actin Monomers, Actin Filaments, and Arp2/3 Complex Define the Roles of WASP Family Proteins and Cortactin in Coordinately Regulating Branched Actin Networks

Calcium Signalling and Calcium Transport in Bone Disease

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