Structural Basis for the Autoinhibition of Focal Adhesion Kinase

Lietha, Daniel; Cai, Xinming; Ceccarelli, Derek F.; Li, Yiqun; Schaller, Michael D.; Eck, Michael J.

doi:10.1016/j.cell.2007.05.041

Cited by 418 publications

(585 citation statements)

References 57 publications

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“…An initial conformational change in FAK may render Y194 accessible for phosphorylation The crystal structure of FAK reveals that Y194 is mostly buried in the structure and is not a good substrate for a kinase (Lietha et al, 2007;Supplementary Figure S2). Thus, it can be assumed that initial conformational changes in FAK would be necessary in order to render this residue accessible for phosphorylation.…”

Section: Resultsmentioning

confidence: 99%

“…To examine this possibility, FAK and its YF mutants were transiently co-expressed with Met and the phosphorylation of FAK on Y577 was measured ( Figure 5a). The Y577 is located within the catalytic domain of FAK and its phosphorylation level has been used to reflect the catalytic activity of FAK (Calalb et al, 1995;Lietha et al, 2007). The Y577 phosphorylation of wild type (wt) FAK was apparently increased by Met.…”

Section: Role Of Y194 Phosphorylation In Fak Activation T-h Chen Et Almentioning

confidence: 99%

“…The Y397 is the major site of FAK autophosphorylation, which creates a high affinity binding site for the Src-homology 2 domain of several proteins including the Src family kinases (Cobb et al, 1994;Schaller et al, 1994;Xing et al, 1994;Eide et al, 1995). Activated Src phosphorylates FAK on multiple sites, including Y576 and Y577, both of which are located in the activation loop within the kinase domain (Calalb et al, 1995;Lietha et al, 2007). The ensuring phosphorylation of FAK by Src on Y576 and Y577 is required for the full enzymatic activity of FAK (Calalb et al, 1995;Lietha et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Activated Src phosphorylates FAK on multiple sites, including Y576 and Y577, both of which are located in the activation loop within the kinase domain (Calalb et al, 1995;Lietha et al, 2007). The ensuring phosphorylation of FAK by Src on Y576 and Y577 is required for the full enzymatic activity of FAK (Calalb et al, 1995;Lietha et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…Crystal structure analysis reveals that the FERM domain of FAK directly binds to its own kinase domain, blocking access to the catalytic cleft and protecting the FAK activation loop from Src phosphorylation (Lietha et al, 2007). At the center of the autoinhibitory interaction between the FERM and kinase domains of FAK, F596 in the kinase domain inserts into a hydrophobic pocket in the FERM domain formed by Y180, M183, V196 and L197 (Lietha et al, 2007). More recently, dynamic changes of FAK from autoinhibited to active conformation were verified in intact cells (Cai et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

et al. 2010

Oncogene

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Focal adhesion kinase (FAK) has a crucial role in integration of signals from integrins and growth factor receptors. In this study, we demonstrate that growth factor receptors including hepatocyte growth factor receptor Met, epidermal growth factor receptor, and platelet-derived growth factor receptor directly phosphorylate FAK on Tyr194 in the FERM domain (band 4.1 and ezrin/radixin/moesin homology domain). Upon binding to Met or phosphoinositides, FAK may undergo conformational changes, which renders Tyr194 accessible for phosphorylation. Substitution of Tyr194 with Phe significantly suppresses the activation of FAK by Met. In contrast, substitution of Tyr194 with Glu (Y194E substitution) leads to constitutive activation of FAK. The phosphorylation of FAK on Tyr194 may cause conformational changes in the FERM domain, which disrupts the intramolecular inhibitory interaction between the FERM and kinase domains of FAK. Moreover, substitution of the basic residues in the 216 KAKTLRK 222 patch in the FERM domain with Ala antagonizes the effect of the Y194E substitution on FAK activation, thus suggesting that the interactions between the phosphorylated Tyr194 and the basic resides in the 216 KAKTLRK 222 patch may allow FAK to be activated through relief of its autoinhibition. Collectively, this study provides the first example to explain how FAK is activated by receptor tyrosine kinases.

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Section: Resultsmentioning

confidence: 99%

Section: Role Of Y194 Phosphorylation In Fak Activation T-h Chen Et Almentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

et al. 2010

Oncogene

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JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease

et al. 2017

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nterleukin 6 (IL-6) plays a central role in the pathogenesis of Castleman disease (CD), 1 an ultrarare lymphoproliferative disorder. Castleman disease may involve a single lymph node (unicentric) or multiple sites (multicentric). Multicentric CD is associated with excessive release of proinflammatory cytokines, hyperproliferation of immune cells, cutaneous manifestations, ascites, pleural effusions, and can result in multiorgan system impairment. 1,2 Clinical and preclinical models have established a central role for IL-6 in symptomatology of multicentric CD. 1,3 These observations have led to development of antibodies targeting IL-6 and IL-6 receptor (IL-6R). 4 Siltuximab, a chimeric monoclonal antibody against human IL-6, has now been approved in the United States for treatment of CD.Even though IL-6 is a central figure in CD, the mechanisms by which IL-6 mediates the activation of the IL-6/ IL-6R/gp130/JAK1 machinery are not completely understood. The current model proposes that the IL-6-mediated signaling cascade is initiated as 2 IL-6 molecules bind to either 2 membrane-bound IL-6Rs or 2 soluble IL-6Rs (sIL-6R). These receptor-ligand (or soluble receptor-ligand) complexes (acting as agonists) then bind to 2 gp130 signaling subunits to form a complete hexameric complex, to which Janus Kinases (JAKs) are constitutively bound. Through an unidentified mechanism, gp130 homodimerization leads to conformational changes and activation of JAK1, presumably through the release of inhibitory intramolecular interactions (Figure 1). 5 Herein, to our knowledge, we report for the first time genomic characterization of CD, identifying a somatic mutation in JAK1 in a patient with CD who attained a long-term complete remission (CR) after siltuximab treatment and discuss the mechanism by which this alteration may potentiate IL-6 signaling. IMPORTANCE Castleman disease (CD) is an ultrarare, interleukin-6 (IL-6)-driven lymphoproliferative disorder whose underlying molecular alterations are unknown. Siltuximab (anti-IL-6 antibody) is approved for treatment of this disease. To our knowledge, genomic sequencing of CD has not been reported. OBJECTIVE To investigate and identify molecular aberration(s) that help explain the exceptional response to siltuximab in a patient with cutaneous CD. DESIGN, SETTING, AND PARTICIPANTSThis case study examines data from comprehensive genomic profiling (using targeted next-generation sequencing) of tissue from a patient with cutaneous CD who demonstrated an exceptional response to siltuximab treated at a National Cancer Institute-designated Comprehensive Cancer Center.INTERVENTIONS Intravenous siltuximab 12 mg/kg every 3 weeks. Tissue from the patient was interrogated by next-generation sequencing (405 genes). Serum was evaluated for IL-6 levels by enzyme-linked immunoassay.MAIN OUTCOMES AND MEASURES Identification of pretreatment serum IL-6 levels and somatic variants that may explain the exceptional response to siltuximab in this patient with cutaneous CD.RESULTS Patient pretreatment serum I...

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Developmental Therapeutics Implications of Next-Generation Sequencing in Human Herpesvirus 8–Negative Castleman Disease

2017

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Castleman disease (CD) comprises a heterogeneous group of lymphoproliferative disorders that share similar histopathological lymph node changes. They are separated into unicentric CD (UCD), which is characterized by lymph node enlargement localized to 1 nodal region and few to no systemic symptoms, or multicentric CD (MCD), which is characterized by generalized lymphadenopathy and often systemic symptoms. Multicentric CD can be further subdivided into human herpesvirus 8 (HHV-8)-positive and HHV-8negative MCD (or idiopathic MCD). In this issue of JAMA Dermatology, Patel et al 1 documented a very elegant use of next-generation sequencing to explain the dramatic response to therapy in a very rare, cutaneous-only manifestation of CD and, by doing so, have provided important therapeutic and future study-design guidance for patients with CD.A perturbed interleukin 6 (IL-6) pathway is a key feature of all types of CD, though CD may present in quite diverse clinical contexts. Unicentric CD is not associated with HHV-8 or human immunodeficiency virus infection and is most often an isolated lymphoproliferative disorder of young adults. Patients are typically asymptomatic and diagnosed when an enlarged lymph node is identified on physical examination or imaging. The histopathological features of lymph nodes from these patients include germinal center hyperplasia, immunoblast and plasma cell accumulation, and increased vascularity. The pathogenesis is poorly understood, but the histopathological findings suggest a disorder characterized by chronic immune activation. Both UCD and MCD have been linked to human or viral interleukin IL-6 excess. Some studies have shown that lymph node excision resulted in relief of symptoms and a decrease in IL-6 levels. 2 Surgical extirpation is curative in 95% of UCD cases. 3 However, the cellular site of elevated IL-6 production has yet to be identified. Interleukin 6 receptor polymorphisms have been found in patients with human immunodeficiency virus-negative CD and are associated with elevated soluble IL-6 receptor levels. 4 Both HHV-8-positive and HHV-8-negative MCD (or idiopathic MCD) manifest as generalized lymphadenopathy with constitutional symptoms that may lead to sepsis, multiorgan failure, and death. The pathogenesis of HHV-8-positive MCD is now understood to be caused by excessive viral IL-6 release triggered by the HHV-8 virus, which also drives human IL-6, IL-10, and vascular endothelial growth factor (VEGF) secretion. In this condition, HHV-8 appears to preferentially infect immunoglobulin M-positive memory B cells, inducing their pro-

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Structural Basis for the Autoinhibition of Focal Adhesion Kinase

Cited by 418 publications

References 57 publications

Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

Phosphorylation of focal adhesion kinase on tyrosine 194 by Met leads to its activation through relief of autoinhibition

JAK1 Genomic Alteration Associated With Exceptional Response to Siltuximab in Cutaneous Castleman Disease

Developmental Therapeutics Implications of Next-Generation Sequencing in Human Herpesvirus 8–Negative Castleman Disease

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