A novel low‐molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth

Shi, Qing; Hjelmeland, Anita B.; Keir, Stephen T.; Song, Linhua; Wickman, Sarah; Jackson, Dowdy; Ohmori, Osamu; Bigner, Darell D.; Friedman, Henry S.; Rich, Jeremy

doi:10.1002/mc.20297

Cited by 174 publications

(154 citation statements)

References 17 publications

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“…This recently developed low molecular weight inhibitor is well characterised as preventing FAK activation via blockade of tyrosine phosphorylation (Halder et al, 2007;Shi et al, 2007). However the application of 500nM TAE226 did not inhibit MG63 maturation in response to LPA/ colchicine and D 3 (data not shown).…”

Section: Discussionmentioning

confidence: 92%

Cytoskeletal reorganisation, 1α,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation

Mansell

Farrar

Jones

et al. 2009

Molecular and Cellular Endocrinology

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Bone tissue is especially receptive to physical stimulation and agents with the capacity to mimic the signalling incurred via mechanical loading on osteoblasts may find an application in a bone regenerative setting. Recently this laboratory revealed that the major serum lipid, lysophosphatidic acid (LPA), cooperated with 125-dihydroxy vitamin D3 (D3) in stimulating human osteoblast maturation. Actin stress fiber accrual in LPA treated osteoblasts would have generated peripheral tension which in turn may have heightened the maturation response of these cells to D3. To test this hypothesis we examined if other agents known to trigger stress fiber accumulation cooperated with D3 in stimulating human osteoblast maturation.Colchicine, nocodazole and LPA all co-operated with D3 to promote MG63 maturation in a MEK dependent manner. In contrast, calpeptin, a direct activator of Rho kinase and stress fiber accumulation did not act with D3 to secure MG63 differentiation. Herein we describe how the signalling elicited via microtubule disruption cooperates with D3 in the development of mature osteoblasts.

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Section: Discussionmentioning

confidence: 92%

Cytoskeletal reorganisation, 1α,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation

Mansell

Farrar

Jones

et al. 2009

Molecular and Cellular Endocrinology

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“…Two groups have recently generated compounds (PF-573,228; PF-562,271; and NVP-TAE226) that are ATP analogs and effectively inhibit the kinase activity of FAK [69,87]. Treatment of cells with these inhibitors results in a decrease in phosphorylation on Y397 along with inhibition of cell migration.…”

Section: Fak As a Therapeutic Target In Cancermentioning

confidence: 99%

Focal adhesion kinase as a regulator of cell tension in the progression of cancer

Tilghman¹,

Parsons²

2008

Seminars in Cancer Biology

145

115

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Growing evidence indicates that critical steps in cancer progression such as cell adhesion, migration, and cell cycle progression are regulated by the composition and organization of the microenvironment. The adhesion of cancer cells to components of the microenvironment and the forces transmitted to the cells via the actinomyosin network and the signaling complexes organized within focal adhesions allow cancer cells to sense the local topography of the extracellular matrix and respond efficiently to proximal growth and migration promoting cues. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is over expressed in a variety of cancers and plays an important role in cell adhesion, migration, and anchorage-dependent growth. In this review, we summarize evidence which implicate FAK in the ability of cells to sense and respond to local forces from the microenvironment through the regulation of adhesion dynamics and actinomyosin contractility, and we discuss the potential roles of FAK as a mechanosensor in the progression of cancer.

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“…FAK inhibitors have been studied for their potential as anticancer therapy and might therefore be "repurposed." 40 In conclusion, our data indicate a role for FAK signaling in proximal tubules during progression of I/R-induced acute renal injury. We propose a model whereby FAK is required for recruitment of JNK to FAs leading to JNKmediated phosphorylation of paxillin at Ser178, thereby facilitating FA turnover during oxidative stress.…”

Section: Discussionmentioning

confidence: 51%

Focal Adhesion Kinase Signaling Mediates Acute Renal Injury Induced by Ischemia/Reperfusion

Qin

Alderliesten

Stokman

et al. 2011

The American Journal of Pathology

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Renal ischemia/reperfusion (I/R) injury is associated with cell matrix and focal adhesion remodeling. Focal adhesion kinase (FAK) is a nonreceptor protein tyrosine kinase that localizes at focal adhesions and regulates their turnover. Here, we investigated the role of FAK in renal I/R injury, using a novel conditional proximal tubule-specific fak-deletion mouse model. Tamoxifen treatment of FAK loxP/loxP //␥GT-Cre-ER T2 mice caused renal-specific fak recombination (FAK ⌬loxP/⌬loxP ) and reduction of FAK expression in proximal tubules. In FAK ⌬loxP/⌬loxP mice compared with FAK loxP/loxP controls, unilateral renal ischemia followed by reperfusion resulted in less tubular damage with reduced tubular cell proliferation and lower expression of kidney injury molecule-1, which was independent from the postischemic inflammatory response. Oxidative stress is involved in the pathophysiology of I/R injury. Primary cultured mouse renal cells were used to study the role of FAK deficiency for oxidative stress in vitro. The conditional fak deletion did not affect cell survival after hydrogen peroxide-induced cellular stress, whereas it impaired the recovery of focal adhesions that were disrupted by hydrogen peroxide. This was associated with reduced c-Jun N-terminal kinase-dependent phosphorylation of paxillin at serine 178 in FAK-deficient cells, which is required for focal adhesion turnover. Our findings support a role for FAK as a novel factor in the initiation of c-Jun N-terminal kinase-mediated cellular stress response during renal I/R injury and suggest FAK as a target in renal injury protection.

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A novel low‐molecular weight inhibitor of focal adhesion kinase, TAE226, inhibits glioma growth

Cited by 174 publications

References 17 publications

Cytoskeletal reorganisation, 1α,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation

Cytoskeletal reorganisation, 1α,25-dihydroxy vitamin D3 and human MG63 osteoblast maturation

Focal adhesion kinase as a regulator of cell tension in the progression of cancer

Focal Adhesion Kinase Signaling Mediates Acute Renal Injury Induced by Ischemia/Reperfusion

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