Integrin α2-mediated ERK and Calpain Activation Play a Critical Role in Cell Adhesion and Motility via Focal Adhesion Kinase Signaling

Sawhney, Rajinder S.; Cookson, Michelle; Omar, Yasin; Hauser, Jennie; Brattain, Michael G.

doi:10.1074/jbc.m600787200

Cited by 95 publications

(87 citation statements)

References 61 publications

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“…These results are consistent with observations in other neurons showing that calpains regulate growth cone formation, motility and guidance in response to Ca 2+ signals (Oshima et al, 1989, Song et al, 1994, Shea et al, 1995, Gitler and Spira, 1998, Robles et al, 2003, Spira et al, 2003. Several molecules that regulate cell adhesion and motility are known calpain substrates including nonreceptor protein kinases (Carragher et al, 2003, Sawhney et al, 2006, phosphatases (Wu et al, 2004, Liu et al, 2005, cytoskeleton-associated proteins (Nixon, 1986, Yamaguchi et al, 1994, Dourdin et al, 2001, Franco et al, 2004, and adhesion molecules (β-integrins) (Huttenlocher et al, 1997, Xi et al, 2006. Additonally, calpains may influence growth cone behavior by modulating tyrosine kinase signaling within the growth cone (Robles et al, 2003).…”

Section: Role Of Calpain Activity On Sgn Neurite Growthsupporting

confidence: 79%

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

Roehm

Woodson

et al. 2008

Molecular and Cellular Neuroscience

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The effect of membrane electrical activity on spiral ganglion neuron (SGN) neurite growth remains unknown despite its relevance to cochlear implant technology. We demonstrate that membrane depolarization delays the initial formation and inhibits the subsequent extension of cultured SGN neurites. This inhibition depends directly on the level of depolarization with higher levels of depolarization causing retraction of existing neurites. Cultured SGNs express subunits for L-type, N-type, and P/Q type voltage-gated calcium channels (VGCCs) and removal of extracellular Ca 2+ or treatment with a combination of L-type, N-type, P/Q-type VGCC antagonists rescues SGN neurite growth under depolarizing conditions. By measuring the fluorescence intensity of SGNs loaded with the fluorogenic calpain substrate t-butoxy carbonyl-Leu-Met-chloromethylaminocoumarin (20 μM), we demonstrate that depolarization activates calpains. Calpeptin (15 μM), a calpain inhibitor, prevents calpain activation by depolarization and rescues neurite growth in depolarized SGNs suggesting that calpain activation contributes to the inhibition of neurite growth by depolarization. Keywords auditory neuron; axon growth; Ca 2+ /calmodulin dependent kinase II

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Section: Role Of Calpain Activity On Sgn Neurite Growthsupporting

confidence: 79%

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

Roehm

Woodson

et al. 2008

Molecular and Cellular Neuroscience

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“…Our results show that ligation of integrin molecules with fibronectin in EC induced mTORC2 dependent phosphorylation of ERK similar to MHC class I molecules. Numerous reports have shown ligation of integrin molecules leads to the phosphorylation of ERK in many cell types, including EC [24][25][26]. However, fibronectin stimulation of beta-1 or beta-3 integrins in cytotoxic T cells fails to activate ERK [27].…”

Section: Discussionmentioning

confidence: 99%

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

Jindra

Jin

Jácamo

et al. 2008

Biochemical and Biophysical Research Communications

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The aim of this study was to characterize the interaction between mTOR and ERK in primary endothelial cells (EC) following MHC class I and integrin ligation. Ligation of MHC class I molecules or integrins on the surface of EC leads to phosphorylation of ERK at Thr202/Tyr204. We utilized small interfering RNA (siRNA) blockade of mTOR and proteins involved in mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) to define a relationship between mTOR and ERK following MHC class I signaling. We found mTORC2 was responsible for MHC class I and integrin induced phosphorylation of ERK at Thr202/Tyr204. We corroborated these results demonstrating that long-term exposure to rapamycin also inhibited ERK pathway activation in response to MHC class I signaling. Our results demonstrate, for the first time, that engagement of either MHC class I or integrin on the surface of EC leads to ERK activation through an mTORC2-dependent pathway. KeywordsMHC; HLA class I; ERK; mTORC2; siRNA; Endothelial cells; Signal transduction mTOR plays an essential role in integrin and MHC class I-induced cell proliferation and survival through formation of two distinct multi-protein molecular complexes, mTORC1 and mTORC2 [1][2][3][4]. mTORC1 consists of mTOR in association with regulatory associated protein of mTOR (Raptor) and GβL [5]. mTORC1 phosphorylates p70 S6 Kinase and eukaryotic initiation factor 4E binding protein 1 which activate translational machinery to increase cell proliferation [6,7]. mTORC2 is composed of mTOR binding to rapamycin insensitive companion of mTOR (Rictor), GβL, stress-activated protein kinase-interacting protein 1 (Sin1) and the newly discovered associations with PRoline-Rich protein 5 (PRR5) or the synonymous protein observed with Rictor 1 (Protor-1), and P-REX1 [8][9][10][11][12]. mTORC2 activates Akt at Ser473, Rac GTPase, cell migration and effects reorganization of the actin cytoskeleton [11][12][13][14]. Recent work utilizing mouse knockout models emphasizes the importance of mTOR for growth and proliferation in development [15,16]. Homozygous mTOR (−/−) mice have * Corresponding author: Fax: + 1 310 206 3216; Email address: ereed@mednet.ucla.edu (E. F. Reed). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. [17,18]. These data show both mTOR complexes are involved in signal transduction leading to cell proliferation, however, the mechanism(s) by which mTORC2 participates in mitogenic signaling remains less well defined. NIH Public AccessERK1/2 are members of a family of serine/threonine kinases activated by a variety of growth factors, cell surface receptors, int...

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“…DSCM expansion also up-regulated integrins α2 and β5 and induced a sustained activation of extracellular signal-regulated kinase-½ (Erk½) and cyclin D1. Since inhibition of integrin α2 suppresses FAK activation and Erk½ phosphorylation (Sawhney et al, 2006), up-regulation of integrin α2 during DSCM expansion might be responsible for a sustained activation of Erk½ in hBMSCs. Up-regulation of TGF-β receptor II during cell expansion and chondrogenic induction might be responsible for an enhanced chondrogenic potential in DSCM expanded hBMSCs.…”

Section: Rejuvenation Effect Of In Vitro Microenvironment On Adult Stmentioning

confidence: 99%

A review of decellularized stem cell matrix: a novel cell expansion system for cartilage tissue engineering

Pei

Li²,

Shoukry³

et al. 2011

eCM

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Cell-based therapy is a promising biological approach for the treatment of cartilage defects. Due to the small size of autologous cartilage samples available for cell transplantation in patients, cells need to be expanded to yield a sufficient cell number for cartilage repair. However, chondrocytes and adult stem cells tend to become replicatively senescent once they are expanded on conventional plastic fl asks. Many studies demonstrate that the loss of cell properties is concomitant with the decreased cell proliferation capacity. This is a signifi cant challenge for cartilage tissue engineering and regeneration. Despite much progress having been made in cell expansion, there are still concerns over expanded cell size and quality for cell transplantation applications. Recently, in vivo investigations in stem cell niches have suggested the importance of developing an in vitro stem cell microenvironment for cell expansion and tissue-specifi c differentiation. Our and other investigators' work indicates that a decellularized stem cell matrix (DSCM) may provide such an expansion system to yield large-quantity and high-quality cells for cartilage tissue engineering and regeneration. This review briefl y introduces key parameters in an in vivo stem cell niche and focuses on our recent work on DSCM for its rejuvenating or reprograming effect on various adult stem cells and chondrocytes. Since research in DSCM is still in its infancy, we are only able to discuss some potential mechanisms of DSCM on cell proliferation and chondrogenic potential. Further investigations of the underlying mechanism and in vivo regeneration capacity will allow this approach to be used in clinics.

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Integrin α2-mediated ERK and Calpain Activation Play a Critical Role in Cell Adhesion and Motility via Focal Adhesion Kinase Signaling

Cited by 95 publications

References 61 publications

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

Membrane depolarization inhibits spiral ganglion neurite growth via activation of multiple types of voltage sensitive calcium channels and calpain

MHC class I and integrin ligation induce ERK activation via an mTORC2-dependent pathway

A review of decellularized stem cell matrix: a novel cell expansion system for cartilage tissue engineering

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