Cross Talk among TGF-  Signaling Pathways, Integrins, and the Extracellular Matrix

Munger, John S.; Sheppard, Dean

doi:10.1101/cshperspect.a005017

Cited by 316 publications

(296 citation statements)

References 107 publications

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“…Similar results are observed by inactivating the gene encoding b3 integrin, treatment with TGF-b neutralizing antibody, or inhibition of the Erk MAPK pathway, suggesting cross-talk between integrins and TGF-b signaling pathways in SSS (Gerber et al 2013). Increased TGF-b signaling in SSS skin might be caused by excessive integrin-mediated TGFb activation and/or increased TGF-b bioavailability and activation of Erk1 and Erk2 MAPK in a b3 integrin-dependent manner, with the bulk of current evidence favoring the latter (Scaffidi et al 2004;Munger and Sheppard 2011;Gerber et al 2013).…”

Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 99%

“…LAPs are translated as prodomains from the same genes and mRNAs encoding the corresponding TGFbs and are referred to as b1-LAP for TGF-b1, b2-LAP for TGF-b2, and b3-LAP for TGF-b3. LAP prodomains are cleaved during posttranslational processing and remain associated with the corresponding TGF-b molecule through noncovalent interactions (Munger and Sheppard 2011). Disruption of noncovalent interactions between TGF-b and LAP molecules, through LAP degradation (Lyons et al 1988;Yu and Stamenkovic 2000), chemical modification, such as that caused by reactive oxygen species or low pH (Lyons et al 1988;Barcellos-Hoff and Dix 1996), and/or through binding-induced conformational change (Munger et al 1997;Shi et al 2011), results in conversion of latent TGF-b into active TGF-b.…”

Section: Extracellular Matrix -Dependent Regulation Of Tgf-b Bioavailmentioning

confidence: 99%

“…TGF-b ligands (TGF-b1, TGF-b2, and TGF-b3) are secreted as biologically inactive latent complexes that are converted into an active form through a tightly regulated process that depends on interactions with components of the ECM (Munger and Sheppard 2011;Robertson and Rifkin 2016). TGF-b latent complexes (referred to as the small latent complex, or SLC) are comprised of TGF-b dimers and latencyassociated peptide (LAP) dimers.…”

Section: Extracellular Matrix -Dependent Regulation Of Tgf-b Bioavailmentioning

confidence: 99%

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TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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The transforming growth factor b (TGF-b) family of signaling molecules, which includes TGF-bs, activins, inhibins, and numerous bone morphogenetic proteins (BMPs) and growth and differentiation factors (GDFs), has important functions in all cells and tissues, including soft connective tissues and the skeleton. Specific TGF-b family members play different roles in these tissues, and their activities are often balanced with those of other TGF-b family members and by interactions with other signaling pathways. Perturbations in TGF-b family pathways are associated with numerous human diseases with prominent involvement of the skeletal and cardiovascular systems. This review focuses on the role of this family of signaling molecules in the pathologies of connective tissues that manifest in rare genetic syndromes (e.g., syndromic presentations of thoracic aortic aneurysm), as well as in more common disorders (e.g., osteoarthritis and osteoporosis). Many of these diseases are caused by or result in pathological alterations of the complex relationship between the TGF-b family of signaling mediators and the extracellular matrix in connective tissues.T he transforming growth factor b (TGF-b) family of cytokines comprises the three TGF-b proteins (TGF-b1, TGF-b2, and TGFb3) and related growth and differentiation factors such as activins, inhibins, bone morphogenic proteins (BMPs), and growth and differentiation factors (GDFs). These molecules play critical roles both in normal development and in several pathological conditions, including inflammation, fibrosis, and cancer (reviewed in Li and Flavell 2006;Gordon and Blobe 2008;Ikushima and Miyazono 2010). This review focuses on the role of these proteins in development and homeostasis of the skeleton and other connective tissues (summarized in Fig. 1) and on the diseases that ensue when these pathways are altered. Aberrant signaling in these pathways has been associated with common connective 6 These authors contributed equally to this work.

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Section: Integrin -Fibrillin Interactions and Overactivation Of Tgf-bmentioning

confidence: 99%

Section: Extracellular Matrix -Dependent Regulation Of Tgf-b Bioavailmentioning

confidence: 99%

Section: Extracellular Matrix -Dependent Regulation Of Tgf-b Bioavailmentioning

confidence: 99%

See 1 more Smart Citation

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

MacFarlane

Haupt

Dietz

et al. 2017

Cold Spring Harb Perspect Biol

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“…4C). 62,71 Many other integrins can recognize various growth factors and act as assisting or enabling receptors for them. 72 In addition to chemical signals, the integrin-based adhesion sites also mediate the effects of mechanical stress from the ECM.…”

Section: 41mentioning

confidence: 99%

Integrins in Wound Healing

Koivisto

Heino

Häkkinen

et al. 2014

Advances in Wound Care

178

154

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“…ALK5 activation is propagated through multiple transduction pathways, several of which rely upon diverse kinase activities [43][44][45]. To determine if any of these known pathways mediate DNp63a phosphorylation, phospho-DNp63a immunofluorescence data from the kinome-wide siRNA screen was re-evaluated.…”

Section: Alk5 Mediates Phosphorylation Of Dnp63amentioning

confidence: 99%

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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Cross Talk among TGF- Signaling Pathways, Integrins, and the Extracellular Matrix

Cited by 316 publications

References 107 publications

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

TGF-β Family Signaling in Connective Tissue and Skeletal Diseases

Integrins in Wound Healing

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

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