Mice Devoid of Fer Protein-Tyrosine Kinase Activity Are Viable and Fertile but Display Reduced Cortactin Phosphorylation

Craig, Andrew W.B.; Zirngibl, Ralph A; Williams, Karen; Cole, L.A.; Greer, Peter A.

doi:10.1128/mcb.21.2.603-613.2001

Cited by 86 publications

(126 citation statements)

References 48 publications

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“…For instance, beside STAT3, Fer was shown to phosphorylate the TATA modulatory factor (44) and to bind the chromatin (45). This raises the controversial issue of the uniqueness of Fer subcellular distribution in cells, exclusively seen in the nucleus or in the cytoplasm (12,42,46) or, else, in both compartments, as shown in prostate cancer cell lines (11) and tissues in the present study. Thus, Fer function may change according not only to cell types but also to localization and interaction with different partners in specific contexts.…”

Section: Discussionmentioning

confidence: 75%

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Zoubeidi

Rocha²,

Zouanat³

et al. 2009

Molecular Cancer Research

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Androgen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgenindependent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6 -mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate

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Section: Discussionmentioning

confidence: 75%

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Zoubeidi

Rocha²,

Zouanat³

et al. 2009

Molecular Cancer Research

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“…O Pasder et al the endogenous Fer (Craig et al, 2001) and to interfere with its activity (Orlovsky et al, 2000). The association of Fer with PP1a might enhance the CDK dependent phosphorylation of PP1a on Thr320.…”

Section: Fer Maintains G1-s Transition In Malignant Cellsmentioning

confidence: 99%

“…Interestingly, mice devoid of an active Fer develop normally and the proliferation of fibroblasts derived from these mice is not impaired in vitro (Craig et al, 2001).…”

Section: Introductionmentioning

confidence: 98%

“…Activation of Fer in these systems could be linked to the modulation of cell-cell and cell-substratum interactions, as Fer was shown to associate with and to phosphorylate adherence molecules (Kim and Wong, 1998;Rosato et al, 1998;Craig et al, 2001;Greer, 2002;Kogata et al, 2003;Miravet et al, 2003;Piedra et al, 2003). Fer was also shown to associate with key cellular regulatory proteins like phosphatidylinositol-3 kinase (Iwanishi et al, 2000), signal transducer and activator of transcription-3 (Stat3) and with the cytoskeletal linker protein plectin (Lunter and Wiche, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

et al. 2006

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Fer is a nuclear and cytoplasmic intracellular tyrosine kinase. Herein we show that Fer is required for cell-cycle progression in malignant cells. Decreasing the level of Fer using the RNA interference (RNAi) approach impeded the proliferation of prostate and breast carcinoma cells and led to their arrest at the G0/G1 phase. At the molecular level, knockdown of Fer resulted in the activation of the retinoblastoma protein (pRB), and this was reflected by profound hypo-phosphorylation of pRB on both cyclindependent kinase CDK4 and CDK2 phosphorylation sites. Dephosphorylation of pRB was not seen upon the direct targeting of either CDK4 or CDK2 expression, and was only partially achieved by the simultaneous depletion of these two kinases. Amino-acid sequence analysis revealed two protein phosphatase 1 (PP1) binding motifs in the kinase domain of Fer and the association of Fer with the pRB phosphatase PP1a was verified using co-immunoprecipitation analysis. Downregulation of Fer potentiated the activation of PP1a and overexpression of Fer decreased the enzymatic activity of that phosphatase. Our findings portray Fer as a regulator of cell-cycle progression in malignant cells and as a potential target for cancer intervention.

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“…First, although various tyrosine kinases can phosphorylate the three tyrosine residues in the carboxy-terminus of cortactin , Fer physically associates with, and regulates N-cadherin junctions (Arregui et al, 2000;Xu et al, 2004). Moreover, cortactin is phosphorylated predominantly by Fer in response to different stimuli (Kim and Wong, 1998;Kapus et al, 2000;Craig et al, 2001), and embryonic fibroblasts derived from mice targeted with a kinase-inactivating mutation in fer exhibit large reductions of tyrosine phosphorylated cortactin (Craig et al, 2001). Accordingly, we determined if N-cadherin ligation promoted Fer activation and if this process led to tyrosine phosphorylation of cortactin and increased adhesion strength.…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of N-Cadherin-associated Cortactin by Fer Kinase Regulates N-Cadherin Mobility and Intercellular Adhesion Strength

Sayegh

Arora

Fan

et al. 2005

MBoC

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Cortactin regulates the strength of nascent N-cadherin-mediated intercellular adhesions through a tyrosine phosphorylation-dependent mechanism. Currently, the functional significance of cortactin phosphorylation and the kinases responsible for the regulation of adhesion strength are not defined. We show that the nonreceptor tyrosine kinase Fer phosphorylates cadherin-associated cortactin and that this process is involved in mediating intercellular adhesion strength. In wild-type fibroblasts N-cadherin ligation-induced transient phosphorylation of Fer, indicating that junction formation activates Fer kinase. Tyrosine phosphorylation of cortactin after N-cadherin ligation was strongly reduced in fibroblasts expressing only catalytically inactive Fer (D743R), compared with wild-type cells. In wild-type cells, Ncadherin-coated bead pull-off assays induced fourfold greater endogenous N-cadherin association than in D743R cells. Fluorescence recovery after photobleaching showed that GFP-N-cadherin mobility at nascent contacts was 50% faster in wild-type than D743R cells. In shear wash-off assays, nascent intercellular adhesion strength was twofold higher in wild-type than D743R cells. Cortactin recruitment to adhesions was independent of Fer kinase activity, but was impacted by N-cadherin ligation-provoked Rac activation. We conclude that N-cadherin ligation induces Rac-dependent cortactin recruitment and Fer-dependent cortactin phosphorylation, which in turn promotes enhanced mobilization and interaction of surface expressed N-cadherin in contacting cells.

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Mice Devoid of Fer Protein-Tyrosine Kinase Activity Are Viable and Fertile but Display Reduced Cortactin Phosphorylation

Cited by 86 publications

References 48 publications

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth

Downregulation of Fer induces PP1 activation and cell-cycle arrest in malignant cells

Phosphorylation of N-Cadherin-associated Cortactin by Fer Kinase Regulates N-Cadherin Mobility and Intercellular Adhesion Strength

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