Serine 732 Phosphorylation of FAK by Cdk5 Is Important for Microtubule Organization, Nuclear Movement, and Neuronal Migration

Xie, Zhigang; Sanada, Kamon; Samuels, Benjamin Adam; Shih, Heather H.; Tsai, Li Huei

doi:10.1016/s0092-8674(03)00605-6

Cited by 289 publications

(305 citation statements)

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“…Because autophosphorylation is the critical step in FAK activation and because sumoylation stimulates dramatically FAK autophosphorylation, PIAS1-catalyzed sumoylation of FAK might represent an additional regulatory step controlling the function of FAK in the nucleus. To establish this function it will be critical to identify possible targets of FAK in the nucleus or possibly in its vicinity (61). In summary, our results show that FAK can be sumoylated in the presence of PIAS1, presumably following nuclear translocation, suggesting that FAK may play a novel role in signaling between the plasma membrane and the nucleus.…”

Section: Sumoylated Fak Is Enriched In the Nuclear Fraction And Sumoymentioning

confidence: 72%

PIAS1-mediated Sumoylation of Focal Adhesion Kinase Activates Its Autophosphorylationn

Kadaré

Toutant

Formstecher

et al. 2003

Journal of Biological Chemistry

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Focal adhesion kinase (FAK) is a protein tyrosine kinase enriched in focal adhesions, which plays a critical role in integrin-dependent cell motility and survival. The crucial step in its activation is autophosphorylation on Tyr-397, which promotes the recruitment of several enzymes including Src family kinases and the activation of multiple signaling pathways. We found in a yeast two-hybrid screen that the N-terminal domain of FAK interacted with protein inhibitor of activated STAT1 (PIAS1). This interaction was confirmed and shown to be direct using in vitro assays. PIAS1 was co-immunoprecipitated with FAK from transfected cells and brain extracts. PIAS1 has recently been recognized as a small ubiquitin-like modifier (SUMO) ligase. In the presence of PIAS1 and SUMO-1, FAK was sumoylated in intact cells, whereas PYK2, a closely related enzyme, was not. Sumoylation occurred on Lys-152, a residue conserved in FAK during evolution. Sumoylated FAK, like PIAS1, was recovered predominantly from the nuclear fraction. Sumoylation did not require the catalytic activity or autophosphorylation of FAK. In contrast, sumoylation increased dramatically the ability of FAK to autophosphorylate in intact cells and in immune precipitate kinase assays. Endogenous FAK was sumoylated in the presence of PIAS1 and SUMO-1 independently of cell adhesion, and autophosphorylation of sumoylated FAK was persistently increased in suspended cells. These observations show that sumoylation controls the activity of a protein kinase and suggest that FAK may play a novel role in signaling between the plasma membrane and the nucleus.Focal adhesion kinase (FAK) 1 is a non-receptor cytoplasmic tyrosine kinase of 125 kDa (1, 2) implicated in integrin-mediated signal transduction (reviewed in Refs. 3-5). It is also activated by a variety of extracellular stimuli including G protein-coupled receptors and growth factor receptors (see Refs. 5 and 6). In adherent mammalian cells in culture FAK is located in focal adhesions (1, 2) and appears important for the regulation of their turnover (7). FAK is critical for adhesion-dependent cell survival (8) and integrin-mediated motility (9). Its physiological importance is demonstrated by the embryonic mortality of FAK knockout mice (7), whereas recent work underlines its role in tumor invasiveness (10). Autophosphorylation at Tyr-397 is a crucial event for FAK biological function, because it creates a high affinity binding site for proteins harboring Src homology 2 (SH2) domains, such as Src and Fyn (11), Grb7 (12), and phosphatidylinositide 3Ј-OH-kinase, which activates the anti-apoptotic Akt pathway (13,14). Following their binding to phospho-Tyr-397, Src or Fyn phosphorylate FAK at other tyrosine residues (15, 16) as well as associated proteins, thereby leading to the activation of several signaling pathways (see 5).In contrast to the recent progress in elucidating the signaling pathways downstream from FAK, relatively little is known about the molecular mechanisms regulating FAK activity. The tyrosine kinase ...

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Section: Sumoylated Fak Is Enriched In the Nuclear Fraction And Sumoymentioning

confidence: 72%

PIAS1-mediated Sumoylation of Focal Adhesion Kinase Activates Its Autophosphorylationn

Kadaré

Toutant

Formstecher

et al. 2003

Journal of Biological Chemistry

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“…Through this exchange paxillin may contribute both to the inhibition of Rho function at the leading edge to promote lamellipodial extension and activation of Cdc42 in the context of cell polarity. Roles for PYK2 or FAK binding to the PKL/GIT and ASAP families of ArfGAPs and the PSGAP/GRAF family of RhoGAPs in influencing Golgi/polarization are currently unknown, although FAK regulation of diaphanous and FAK phosphorylation by cdk5 have been implicated in microtubule stabilization and maintenance of the leading edge (197,198,309).…”

Section: B P21-gtpase Regulation and Migrationmentioning

confidence: 99%

Paxillin: Adapting to Change

Brown¹,

Turner²

2004

Physiological Reviews

551

728

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Molecular scaffold or adaptor proteins facilitate precise spatiotemporal regulation and integration of multiple signaling pathways to effect the optimal cellular response to changes in the immediate environment. Paxillin is a multidomain adaptor that recruits both structural and signaling molecules to focal adhesions, sites of integrin engagement with the extracellular matrix, where it performs a critical role in transducing adhesion and growth factor signals to elicit changes in cell migration and gene expression.

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“…(3) Layer formation of cortical neurons is disrupted in Cdk5 Ϫ/Ϫ mouse brains (Ohshima et al, 1996;Gilmore et al, 1998). Several Cdk5 substrates, such as FAK, doublecortin, p27 kip1 , drebrin, and Mst3, have been reported as possible downstream pathways (Xie et al, 2003;Tanaka et al, 2004;Kawauchi et al, 2006;Tanabe et al, 2014;Tang et al, 2014). Considering that Cdk5 is a membrane-bound kinase, however, it is also likely that Cdk5 regulates neuronal migration through membrane proteins and/or membrane trafficking.…”

Section: Discussionmentioning

confidence: 99%

“…Interconversion of the active and inactive states is mediated by guanine nucleotide exchange factors (GEFs), which exchange GDP for GTP and GTPase-activating proteins (GAPs), which stimulate GTP hydrolysis. Therefore, the regulation mechanism of each GEF or GAP for each Rab must be individually described, but only a few cases have been reported (Xu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Cdk5 Regulation of the GRAB-Mediated Rab8-Rab11 Cascade in Axon Outgrowth

et al. 2016

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Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface expansion. Two membrane sources for axon outgrowth are suggested: Golgi secretary vesicles and endocytic recycling endosomes. In non-neuronal cells, trafficking of secretary vesicles from Golgi is regulated by Rab8, a member of Rab small GTPases, and that of recycling endosomes is by Rab11, another member of Rabs. However, whether these vesicles are coordinately or independently transported in growing axons is unknown. Herein, we find that GRAB, a guanine nucleotide exchange factor for Rab8, is a novel regulator of axon outgrowth. Knockdown of GRAB suppressed axon outgrowth of cultured mouse brain cortical neurons. GRAB mediates the interaction between Rab11A and Rab8A, and this activity is regulated by phosphorylation at Ser169 and Ser180 by Cdk5-p35. The nonphosphorylatable GRAB mutant S169/180A promoted axonal outgrowth to a greater extent than did the phosphomimetic GRAB mutant S169/180D. Phosphorylation of GRAB suppressed its guanine nucleotide exchange factor activity and its ability to recruit Rab8A-to Rab11A-positive endosomes. In vivo function of GRAB and its Cdk5-phophorylation were shown in migration and process formation of developing neurons in embryonic mouse brains. These results indicate that GRAB regulates axonal outgrowth via activation and recruitment of Rab8A-to Rab11A-positive endosomes in a Cdk5-dependent manner.

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Serine 732 Phosphorylation of FAK by Cdk5 Is Important for Microtubule Organization, Nuclear Movement, and Neuronal Migration

Cited by 289 publications

References 60 publications

PIAS1-mediated Sumoylation of Focal Adhesion Kinase Activates Its Autophosphorylationn

PIAS1-mediated Sumoylation of Focal Adhesion Kinase Activates Its Autophosphorylationn

Paxillin: Adapting to Change

Cdk5 Regulation of the GRAB-Mediated Rab8-Rab11 Cascade in Axon Outgrowth

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