Abstract 351: Focal Adhesion Kinase Promotes Tissue Destruction in Aortic Dissection in Mice

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Ryohei Majima ◽  
Hiroki Aoki ◽  
Eichi Nakao ◽  
Yohei Hashimoto ◽  
Sohei Ito ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Suppressive Effect ◽  
Lesion Length ◽  
Ang Ii ◽  
Tissue Destruction ◽  
Potential Therapeutic Target ◽  
Mouse Aorta

Aortic dissection (AD) is a fatal disease due to the sudden destruction of the aortic medial layer. Currently, Molecular pathogenesis of AD is unknown. We investigated the role of focal adhesion kinase (FAK), a mechanosensitive signal transducer, in AD pathogenesis. We created a mouse model of AD with a continuous infusion of beta-aminopropionitrile (150 mg/kg/day), a collagen crosslink inhibitor, and angiotensin II (1,000 ng/kg/min) (BAPN + Ang II) by osmotic pumps. This AD model showed about 60% mortality within 2 weeks due to AD rupture. Immunohistochemical staining for activated FAK revealed that FAK was inactive in normal mouse aorta, but was strongly activated in the aortic walls after BAPN + Ang II infusion. Immunofluorescence staining showed that FAK was activated mainly in smooth muscle cells after the BAPN + Ang II challenge. Western blot analysis revealed that FAK was activated in 3 days after BAPN + Ang II infusion before AD development, followed by transient reduction at day 7, and re-activation after AD development at day 14. We examined the effect of PND-1186, an orally available FAK inhibitor, on the severity as determined by the AD lesion length and the mortality of AD. Mice were administered with either vehicle or PND-1186 (150 mg/kg twice daily by oral gavage) during the BAPN + Ang II challenge (n=20 for each group). Administration of PND-1186 resulted in significant reduction in the lesion length of AD (vehicle; 12.5 ± 1.65 mm, PND; 7.46 ± 1.88 mm, P<0.05). The suppressive effect of PND-1186 was most significant in the aortic arch (vehicle; 2.13 ± 0.29 mm, PND; 0.85 ± 0.22 mm, P<0.01). Furthermore, PND-1186 significantly improved the survival rate of mice from 40.0% to 80.0% (P<0.01). Transcriptome analysis indicated that destruction and inflammation of tissue were suppressed by PND-1186 administration. These findings indicated that FAK plays an important role in AD pathogenesis, possibly by transducing the pathological stress to the tissue destructive response in the aortic walls. We propose that FAK is a potential therapeutic target to limit the fatal destruction of aortic walls in AD.

Focal Adhesion Kinase in Ovarian Cancer: A Potential Therapeutic Target for Platinum and Taxane-Resistant Tumors

2019 ◽  
Vol 19 (3) ◽  
pp. 179-188 ◽  
Author(s):  
Arkene Levy ◽  
Khalid Alhazzani ◽  
Priya Dondapati ◽  
Ali Alaseem ◽  
Khadijah Cheema ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Tumor Stage ◽  
Current Status ◽  
Potential Therapeutic Target ◽  
Resistant Disease ◽  
Development Of Resistance ◽  
And Function ◽  
Mdr 1

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase, which is an essential player in regulating cell migration, invasion, adhesion, proliferation, and survival. Its overexpression and activation have been identified in sixty-eight percent of epithelial ovarian cancer patients and this is significantly associated with higher tumor stage, metastasis, and shorter overall survival of these patients. Most recently, a new role has emerged for FAK in promoting resistance to taxane and platinum-based therapy in ovarian and other cancers. The development of resistance is a complex network of molecular processes that make the identification of a targetable biomarker in platinum and taxane-resistant ovarian cancer a major challenge. FAK overexpression upregulates ALDH and XIAP activity in platinum-resistant and increases CD44, YB1, and MDR-1 activity in taxaneresistant tumors. FAK is therefore now emerging as a prognostically significant candidate in this regard, with mounting evidence from recent successes in preclinical and clinical trials using small molecule FAK inhibitors. This review will summarize the significance and function of FAK in ovarian cancer, and its emerging role in chemotherapeutic resistance. We will discuss the current status of FAK inhibitors in ovarian cancers, their therapeutic competencies and limitations, and further propose that the combination of FAK inhibitors with platinum and taxane-based therapies could be an efficacious approach in chemotherapeutic resistant disease.

scholarly journals SAT-604 The Role of the Focal Adhesion Kinase Family in Leptin Receptor Signaling

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Colleen Hadley ◽  
Isin Cakir ◽  
Roger D Cone
Keyword(s):  
Food Intake ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Leptin Receptor ◽  
Kinase Activity ◽  
Cytokine Receptor ◽  
Receptor Signaling ◽  
Kinase Family ◽  
Stat3 Phosphorylation

Abstract Overweight and obesity are global concerns affecting nearly one third of the world population. These conditions are characterized by increased adiposity and are accompanied by a proportional increase in circulating leptin, an anorexigenic adipokine. Leptin is responsible for signaling peripheral energy status to the central nervous system to modulate food intake and energy expenditure. As such, neurons within the hypothalamus expressing the long isoform of leptin receptor (LepRb), a type I cytokine receptor, are primarily responsible for mediating the effects of leptin, which signal predominantly through the JAK2-STAT3 transduction mechanism. STAT3 is a latent transcription factor activated upon phosphorylation, which triggers its homodimerization and nuclear translocation. Evidence, however, for JAK2-independent, STAT3-dependent leptin receptor signaling mechanisms exist. FAK (focal adhesion kinase, Ptk2) and Pyk2 (protein tyrosine kinase 2b, Ptk2b) are a subset of nonreceptor protein tyrosine kinases and comprise the focal adhesion kinase family. FAK and Pyk2 are implicated in the regulation of cytokine receptor signaling. Furthermore, Pyk2 knockout mice have an obesity prone phenotype. Here, we studied the role of the focal adhesion kinases in leptin receptor signaling using genetic and pharmacological approaches. We found that overexpression of Pyk2 or FAK increased STAT3 phosphorylation (activation). Overexpression of a FAK or Pyk2 construct with impaired kinase activity, however, attenuated STAT3 phosphorylation, suggesting the increase in STAT3 phosphorylation is largely dependent upon kinase activity of FAK/Pyk2. Treatment of cells with a small molecule dual inhibitor of FAK and Pyk2 (PF431396) attenuated leptin-induced STAT3 phosphorylation in a mouse hypothalamic cell line. Importantly, this effect is independent of JAK2, as PF treatment of two independent JAK2-deficient cell lines exhibited similar attenuation of leptin-induced STAT3 phosphorylation. To assess the physiological relevance of FAK/Pyk2 in leptin receptor signaling in vivo, we administered PF compound to the lateral ventricle of 24-hour fasted lean wild-type mice followed by peripheral leptin administration. Intracerebroventricular (ICV) administration of PF suppressed the anorectic effect of leptin as evidenced by impaired inhibition of food intake upon refeeding. Accordingly, analysis of total hypothalamic lysates from these mice showed ICV PF impaired leptin-induced STAT3 phosphorylation. Taken together, these data suggest that Pyk2 and/or FAK play a role in leptin signal transduction.

scholarly journals Inhibitory effects of Yangzheng Xiaoji on angiogenesis and the role of the focal adhesion kinase pathway

2012 ◽  
Vol 41 (5) ◽  
pp. 1635-1642 ◽  
Author(s):  
WEN G. JIANG ◽  
LIN YE ◽  
KE JI ◽  
NATASHA FREWER ◽  
JIAFU JI ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Inhibitory Effects ◽  
Kinase Pathway

scholarly journals Integrin-mediated Activation of Focal Adhesion Kinase Is Required for Signaling to Jun NH2-terminal Kinase and Progression through the G1 Phase of the Cell Cycle

1999 ◽  
Vol 145 (7) ◽  
pp. 1461-1470 ◽  
Author(s):  
Maja Oktay ◽  
Kishore K. Wary ◽  
Michael Dans ◽  
Raymond B. Birge ◽  
Filippo G. Giancotti
Keyword(s):  
Cell Cycle ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
G1 Phase ◽  
Normal Cells ◽  
Jnk Signaling ◽  
Stringent Control ◽  
No Activation ◽  
Stimulation Of

The extracellular matrix exerts a stringent control on the proliferation of normal cells, suggesting the existence of a mitogenic signaling pathway activated by integrins, but not significantly by growth factor receptors. Herein, we provide evidence that integrins cause a significant and protracted activation of Jun NH2-terminal kinase (JNK), while several growth factors cause more modest or no activation of this enzyme. Integrin-mediated stimulation of JNK required the association of focal adhesion kinase (FAK) with a Src kinase and p130CAS, the phosphorylation of p130CAS, and subsequently, the recruitment of Crk. Ras and PI-3K were not required. FAK–JNK signaling was necessary for proper progression through the G1 phase of the cell cycle. These findings establish a role for FAK in both the activation of JNK and the control of the cell cycle, and identify a physiological stimulus for JNK signaling that is consistent with the role of Jun in both proliferation and transformation.

scholarly journals In Vivo Role of Focal Adhesion Kinase in Regulating Pancreatic  -Cell Mass and Function Through Insulin Signaling, Actin Dynamics, and Granule Trafficking

Diabetes ◽  
2012 ◽  
Vol 61 (7) ◽  
pp. 1708-1718 ◽  
Author(s):  
E. P. Cai ◽  
M. Casimir ◽  
S. A. Schroer ◽  
C. T. Luk ◽  
S. Y. Shi ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Insulin Signaling ◽  
Cell Mass ◽  
Actin Dynamics ◽  
Pancreatic Cell ◽  
And Function

scholarly journals Physiologic Role of Decidual .BETA.1 Integrin and Focal Adhesion Kinase in Embryonic Implantation

2003 ◽  
Vol 50 (2) ◽  
pp. 189-198 ◽  
Author(s):  
HIDEKI HANASHI ◽  
SHIGETATSU SHIOKAWA ◽  
YOSHIHIRO AKIMOTO ◽  
KEN SAKAI ◽  
KEIJI SAKAI ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Beta 1 Integrin ◽  
Physiologic Role

Involvement of AT2 receptors at NRVL in tonic baroreflex suppression by endogenous angiotensins

1997 ◽  
Vol 272 (5) ◽  
pp. H2204-H2210 ◽  
Author(s):  
K. S. Lin ◽  
J. Y. Chan ◽  
S. H. Chan
Keyword(s):  
Suppressive Effect ◽  
Angiotensin Receptors ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Inhibitory Modulation ◽  
Sprague Dawley Rats ◽  
Peptide Antagonist ◽  
Endogenous Activity ◽  
At2 Receptors

We evaluated the role of endogenous angiotensin II and III (ANG II and ANG III) at the rostral nucleus reticularis ventrolateralis (NRVL) in the modulation of baroreceptor reflex (BRR) response and the subtype of angiotensin receptors involved in this process. Adult male Sprague-Dawley rats anesthetized and maintained with pentobarbital sodium were used. Exogenous application of ANG II or ANG III (10, 20, or 40 pmol) by bilateral microinjection into the NRVL significantly suppressed the BRR response to transient hypertension induced by phenylephrine (5 micrograms/kg i.v.). The suppressive effect of ANG II (20 pmol) was reversed by an equimolar dose (1.6 nmol) of its peptide antagonist, [Sar1, Ile8]ANG II, and the nonpeptide antagonists for AT1 and AT2 receptors, losartan and PD-123319, respectively. On the other hand, the inhibitory action of ANG III (20 pmol) was blunted by its peptide antagonist. [Ile7]ANG III or PD-123319, but not by losartan. Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NRVL of [Sar1, Ile8]ANG II, [Ile7]ANG III, or PD-123319 elicited an appreciable enhancement of the BRR response, whereas losartan produced minimal effect. These results suggest that, under physiological conditions, both endogenous ANG II and ANG III may exert a tonic inhibitory modulation on the BRR response by acting selectively on the AT2 receptors at the NRVL.

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