scholarly journals Low Mr Phosphotyrosine Protein Phosphatase Associates and Dephosphorylates p125 Focal Adhesion Kinase, Interfering with Cell Motility and Spreading

2002 ◽  
Vol 277 (44) ◽  
pp. 41631-41636 ◽  
Author(s):  
Stefania Rigacci ◽  
Elisabetta Rovida ◽  
Persio Dello Sbarba ◽  
Andrea Berti
Keyword(s):  
Cell Motility ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Protein Phosphatase ◽  
Phosphotyrosine Protein Phosphatase

Focal Adhesion Kinase Inactivation Reduces the Development of Acute Leukemia and Partially Rescues Hematopoietic Stem Cell Defects in Pten-Knockout Mice

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 864-864
Author(s):  
Dewen You ◽  
Andrew Volk ◽  
Clare Sun ◽  
Junping Xin ◽  
Geunhyoung Ha ◽  
...  
Keyword(s):  
Focal Adhesion Kinase ◽  
Phosphatase Activity ◽  
Focal Adhesion ◽  
Protein Phosphatase ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Critical Role ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Polycytidylic Acid

Abstract Abstract 864 Phosphatase and tensin homolog on chromosome 10 (Pten) is a tumor suppressor which possesses both lipid and protein phosphatase activities. Mutations and epigenetic inactivations of the Pten gene are commonly detected in a large number of tissue malignancies, including leukemias and lymphomas. Studies using Hematopoietic Pten-knockout in adult mice (Pten−/−) have demonstrated that Pten plays a critical role in maintaining the homeostasis of bone marrow (BM) hematopoiesis. Pten inactivation promotes the proliferation and peripheral mobilization of BM hematopoietic stem cells (HSCs). Pten−/− mice develop myeloproliferative disorders (MPD) within days, followed by acute leukemic transformation. Most previous studies attributed such phenotypic changes observed in Pten−/− mice to excessive activation of the PI3K/AKT/mTOR signal, a consequence of the loss of Pten's lipid phosphatase activity. However, the role of Pten's protein phosphatase activity in the regulation of HSCs and leukemogenesis is not well studied. Focal adhesion kinase (Fak) is a critical substrate for the protein phosphatase activity of Pten. Dysregulation of Fak has been observed in many cancers, including acute myeloid leukemias (AML) and acute lymphocytic leukemias (ALL). Therefore, we postulated that Fak might play a pivotal role in the development and progression of leukemia following Pten deletion. To test this hypothesis, we generated Mx1-Cre+Ptenfl/flFakfl/fl mice (an interferon-inducible Pten and Fak compound-knockout, Pten−/−Fak−/−) in which both the Pten and Fak genes in the hematopoietic system are deleted upon injection of polyinosinic-polycytidylic acid (pI-pC). Our results showed that the genetic inactivation of Fak can partially rescue HSC defects associated with Pten deficiency. We found that peripheral mobilization of HSCs in Pten−/−Fak−/− mice is significantly reduced compared to Pten−/− mice. As a consequence, more long-term HSCs (LT-HSCs) are preserved in the BM of Pten−/−Fak−/− mice compared to Pten−/− mice. Transplantation studies suggested that the hematopoietic reconstitutive capacity of Pten−/−Fak−/− HSCs is significantly improved compared to Pten−/− HSCs. Although Fak deletion fails to prevent the development of MPD in Pten−/− mice, Fak deletion does significantly reduce the frequency of AML/ALL, also significantly delays the onset of AML/ALL in comparison to Pten−/− mice. This study suggests that Fak might be a potential target for preventing the MPD-to-AML/ALL transformation and therefore blocking the Fak activity may hold a promise for a novel anti-leukemia therapy. The molecular mechanisms underlying the phenotype restoration of Pten−/− mice by Fak deletion in the hematopoietic system are actively being studied in our laboratory. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cell-cycle-dependent association of protein phosphatase 1 and focal adhesion kinase

2001 ◽  
Vol 358 (2) ◽  
pp. 407 ◽  
Author(s):  
Marco FRESU ◽  
Mariarita BIANCHI ◽  
J. Thomas PARSONS ◽  
Emma VILLA-MORUZZI
Keyword(s):  
Cell Cycle ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Cycle Dependent

scholarly journals Targeting Pyk2 to β1-Integrin–Containing Focal Contacts Rescues Fibronectin-Stimulated Signaling and Haptotactic Motility Defects of Focal Adhesion Kinase–Null Cells

2001 ◽  
Vol 152 (1) ◽  
pp. 97-110 ◽  
Author(s):  
Candice K. Klingbeil ◽  
Christof R. Hauck ◽  
Datsun A. Hsia ◽  
K.C. Jones ◽  
Shannon R. Reider ◽  
...  
Keyword(s):  
Cell Motility ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Β1 Integrin ◽  
Focal Contact ◽  
Contact Sites ◽  
Focal Contacts ◽  
Tyrosine Kinase 2 ◽  
Transient Overexpression ◽  
The Impact

Focal adhesion kinase–null (FAK−/−) fibroblasts exhibit morphological and motility defects that are reversed by focal adhesion kinase (FAK) reexpression. The FAK-related kinase, proline-rich tyrosine kinase 2 (Pyk2), is expressed in FAK−/− cells, yet it exhibits a perinuclear distribution and does not functionally substitute for FAK. Chimeric Pyk2/FAK proteins were created and expressed in FAK−/− cells to determine the impact of Pyk2 localization to focal contacts. Whereas an FAK/Pyk2 COOH-terminal (CT) domain chimera was perinuclear distributed, stable expression of a Pyk2 chimera with the FAK-CT domain (Pyk2/FAK-CT) localized to focal contact sites and enhanced fibronectin (FN)-stimulated haptotactic cell migration equal to FAK-reconstituted cells. Disruption of paxillin binding to the FAK-CT domain (S-1034) inhibited Pyk2/FAK-CT localization to focal contacts and its capacity to promote cell motility. Paxillin binding to the FAK-CT was necessary but not sufficient to mediate the indirect association of FAK or Pyk2/FAK-CT with a β1-integrin–containing complex. Both FAK and Pyk2/FAK-CT but not Pyk2/FAK-CT S-1034 reconstituted FAK−/− cells, exhibit elevated FN-stimulated extracellular signal–regulated kinase 2 (ERK2) and c-Jun NH2-terminal kinase (JNK) kinase activation. FN-stimulated FAK or Pyk2/FAK-CT activation enhanced both the extent and duration of FN-stimulated ERK2 activity which was necessary for cell motility. Transient overexpression of the FAK-CT but not FAK-CT S-1034 domain inhibited both FN-stimulated ERK2 and JNK activation as well as FN-stimulated motility of Pyk2/FAK-CT reconstituted cells. These gain-of-function studies show that the NH2-terminal and kinase domains of Pyk2 can functionally substitute for FAK in promoting FN-stimulated signaling and motility events when localized to β-integrin–containing focal contact sites via interactions mediated by the FAK-CT domain.

scholarly journals Integrin α4β1 Promotes Focal Adhesion Kinase-Independent Cell Motility via α4 Cytoplasmic Domain-Specific Activation of c-Src

2005 ◽  
Vol 25 (21) ◽  
pp. 9700-9712 ◽  
Author(s):  
Datsun A. Hsia ◽  
Ssang-Taek Lim ◽  
Joie A. Bernard-Trifilo ◽  
Satyajit K. Mitra ◽  
Sakae Tanaka ◽  
...  
Keyword(s):  
Cell Motility ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
Tyrosine Phosphatase ◽  
Cytoplasmic Domain ◽  
Dominant Negative ◽  
Receptor Protein ◽  
Rac Gtpase ◽  
Null Cell ◽  
Signaling Complex

ABSTRACT The fibronectin binding integrins α5β1 and α4β1 generate signals pivotal for cell migration through distinct yet undefined mechanisms. For α5β1, β1-mediated activation of focal adhesion kinase (FAK) promotes c-Src recruitment to FAK and the formation of a FAK-Src signaling complex. Herein, we show that FAK expression is essential for α5β1-stimulated cell motility and that exogenous expression of human α4 in FAK-null fibroblasts forms a functional α4β1 receptor that promotes robust cell motility equal to the α5β1 stimulation of wild-type and FAK-reconstituted fibroblasts. α4β1-stimulated FAK-null cell spreading and motility were dependent on the integrity of the α4 cytoplasmic domain, independent of direct paxillin binding to α4, and were not affected by PRNK expression, a dominant-negative inhibitor of Pyk2. α4 cytoplasmic domain-initiated signaling led to a ∼4-fold activation of c-Src which did not require paxillin binding to α4. Notably, α4-stimulated cell motility was inhibited by catalytically inactive receptor protein-tyrosine phosphatase α overexpression and blocked by the p50Csk phosphorylation of c-Src at Tyr-529. α4β1-stimulated cell motility of triple-null Src−/−, c-Yes−/−, and Fyn−/− fibroblasts was dependent on c-Src reexpression that resulted in p130Cas tyrosine phosphorylation and Rac GTPase loading. As p130Cas phosphorylation and Rac activation are common downstream targets for α5β1-stimulated FAK activation, our results support the existence of a novel α4 cytoplasmic domain connection leading to c-Src activation which functions as a FAK-independent linkage to a common motility-promoting signaling pathway.

p85 β-PIX is required for cell motility through phosphorylations of focal adhesion kinase and p38 MAP kinase

2005 ◽  
Vol 307 (2) ◽  
pp. 315-328 ◽  
Author(s):  
Jangsoon Lee ◽  
In Duk Jung ◽  
Won Keun Chang ◽  
Chang Gyo Park ◽  
Do Yeun Cho ◽  
...  
Keyword(s):  
Cell Motility ◽  
Map Kinase ◽  
Focal Adhesion Kinase ◽  
Focal Adhesion ◽  
P38 Map Kinase

scholarly journals FAK is required for the assembly of podosome rosettes

2011 ◽  
Vol 195 (1) ◽  
pp. 113-129 ◽  
Author(s):  
Yi-Ru Pan ◽  
Chien-Lin Chen ◽  
Hong-Chen Chen
Keyword(s):  
Extracellular Matrix ◽  
Cell Motility ◽  
Focal Adhesion Kinase ◽  
Intermediate Filaments ◽  
Focal Adhesion ◽  
Tumor Invasion ◽  
Matrix Degradation ◽  
Membrane Structures ◽  
Negative Role ◽  
Invasive Cell

Podosomes are dynamic actin-enriched membrane structures that play an important role in invasive cell motility and extracellular matrix degradation. They are often found to assemble into large rosettelike structures in highly invasive cells. However, the mechanism of this assembly remains obscure. In this study, we identified focal adhesion kinase (FAK) as a key molecule necessary for assembly. Moreover, phosphorylation of p130Cas and suppression of Rho signaling by FAK were found to be important for FAK to induce the assembly of podosome rosettes. Finally, we found that suppression of vimentin intermediate filaments by FAK facilitates the assembly of podosome rosettes. Collectively, our results strongly suggest a link between FAK, podosome rosettes, and tumor invasion and unveil a negative role for Rho signaling and vimentin filaments in podosome rosette assembly.

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