The ALK‐5 inhibitor A‐83‐01 inhibits Smad signaling and epithelial‐to‐mesenchymal transition by transforming growth factor‐β

Tojo, Masayoshi; Hamashima, Yoshio; Hanyu, Aki; Kajimoto, Tetsuya; Saitoh, Masao; Miyazono, Kohei; Node, Manabu; Imamura, Takeshi

doi:10.1111/j.1349-7006.2005.00103.x

Cited by 291 publications

(247 citation statements)

References 26 publications

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“…Results indicate that TGFb stimulation increases phosphoDNp63a levels within one hour, indicating signaling kinetics similar to SMAD2 phosphorylation. This phosphorylation was inhibited by A83-01, a selective ALK5 kinase inhibitor [36] ( Figure 2B), which supports the assertion that TGFb mediated DNp63a phosphorylation requires ALK5 activity. This observation coupled to the fact that ALK5 possesses no inherent TGFBbinding capacity suggested the involvement of TGFbR2.…”

Section: Tgfb Stimulates Alk5-mediated Phosphorylation Of Dnp63 a Viasupporting

confidence: 68%

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

DeCastro¹,

Cherukuri²,

DiRenzo³

2012

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE December 2012 REPORT TYPE Annual Summary DATES COVERED 15November2011-14November2012 TITLE AND SUBTITLE Regulation of Mammary Stem Cell Quiescence via Post-Translational 5a. CONTRACT NUMBERModification of DeltaNp63alpha. 5b. GRANT NUMBERW81XWH-11-1-0043 5c. PROGRAM ELEMENT NUMBER AUTHOR(S)Andrew. J DeCastro, B.S., Pratima Cherukuri, M.S., James DiRenzo, PhD.5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: Andrew.J.DeCastro@Dartmouth.edu 5f. WORK UNIT NUMBER PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) PERFORMING ORGANIZATION REPORT NUMBERDartmouth College, Hanover, NH 03755 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S)U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis document is the Annual Summary Report on the training grant awarded to Andrew DeCastro entitled Regulation of Mammary Stem Cell Quiescence via Post-translational Modification of ∆NP63α. Here, we report our findings of the effects of TGFβ (previously validated as a kinase in our kinome screen) mediated phosphorylation of ∆NP63α on stem cell behavior and mitotic activity. Task 1 aims to determine the effects of wild-type, phospho-ablative and phospho-mimetic alleles of ∆NP63α phosphorylation on stem cell behavior in vitro. Thus far, we demonstrate that stem cell enriched populations, as indicated by ALDH1 activity, contain higher concentrations of ∆NP63α mRNA. In addition, we demonstrate that the anti-clonogenic effects of TGFβ are mediated through phosphorylation of ∆NP63α, which is rescued via ectopic expression of the phospho-ablative mutant ∆NP63α-AA. Task 2 aims to identify putative ∆NP63α-kinases and determine their role in mitotic activation. Here we further characterize TGFβ-mediated phosphorylation of ∆NP63α. We demonstrate that TGFβ phosphorylation of ∆NP63α is a destabilizing event, and dependent on the proteasomal degradation pathway. We also report a non-canonical pathway in which ALK5 (TGF...

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Section: Tgfb Stimulates Alk5-mediated Phosphorylation Of Dnp63 a Viasupporting

confidence: 68%

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

DeCastro¹,

Cherukuri²,

DiRenzo³

2012

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“…The kinase inhibitor A-83-01 indicates the importance of ALK5 for both processes (Tojo et al, 2005). The experiments using R1B and DR26 cells with impaired TGF-b receptor functions show that the mechanism requires both kinases to function.…”

Section: Discussionmentioning

confidence: 99%

Extracellular matrix-induced transforming growth factor-β receptor signaling dynamics

Garamszegi

Samavarchi-Tehrani

et al. 2010

Oncogene

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Matrix remodeling, degradation, inflammation and invasion liberate peptide fragments that can subsequently interact with cells in an attachment-independent manner. Such 'soluble' matrix components, including collagens, fibronectin and laminin, induced Smad activation (termed crosstalk signaling), which follows a similar chronological sequence and R-Smad specificity as induced by transforming growth factor (TGF)-b1. Smad4 nuclear translocation occurred in response to collagen binding, indicating downstream signal propagation. TGF-b scavenging antibody affected only TGF-b1, but not crosstalk-induced responses. TGF-b type II receptor mutation (DR26D25), which is deficient in TGF-b type I receptor recruitment to the ligand, induced a heterotetramer signaling complex, and propagated Smad2 activation only through collagen induction and not TGF-b signaling. Consequentially, TGF-b ligand participation is not required for crosstalk signaling. This signaling requires a functional integrin b1 receptor as showed by RNA interference. Co-immunoprecipitation (co-IP) and fluorescent microscopy indicate the involvement of focal adhesion kinase (FAK) and Src activity in collagen-induced signal propagation, and suggest a membrane signaling complex formation that includes both TGF-b receptors and integrins. The related gene expressional responses are distinct from that evoked by TGF-b1, supporting its separate function. This signaling mechanism expands and partially explains TGFb receptor dynamics and consequential signaling diversityrelated gene expressional plasticity.

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“…Equally, SD-208 inhibits TGFb-mediated migration and invasion; however, viability and proliferation are not reduced in all the tumor cell models studied so far (Hayashi et al, 2004;Uhl et al, 2004). Additional small molecule inhibitors of TGFb-signaling such as SB-505124 (DaCosta Byfield et al, 2004) and A-83-01 (Tojo et al, 2005) have been shown to modulate TGF-familymember-mediated signaling, but the applicability of these substances for the treatment of HCC cells has not been shown so far.…”

Section: Therapeutic Approachesmentioning

confidence: 99%

Dysregulation of growth factor signaling in human hepatocellular carcinoma

2006

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The ALK‐5 inhibitor A‐83‐01 inhibits Smad signaling and epithelial‐to‐mesenchymal transition by transforming growth factor‐β

Cited by 291 publications

References 26 publications

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

Regulation of Mammary Stem Cell Quiescence via Post-Translational Modification of DeltaNp63alpha

Extracellular matrix-induced transforming growth factor-β receptor signaling dynamics

Dysregulation of growth factor signaling in human hepatocellular carcinoma

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