Protein Kinase A Modulates Transforming Growth Factor-β Signaling through a Direct Interaction with Smad4 Protein

Abstract

Background: TGF␤ induces a Smad3-Smad4 complex and PKA-R interaction. Results: We define interaction domains between Smad4 and PKA-R required for TGF␤-mediated cell growth and EMT regulation. Conclusion: An interaction between Smad4 and PKA-R regulates TGF␤ signaling. Significance: A novel cross-talk mechanism between TGF␤ and PKA signaling is identified that is critical for execution of TGF␤-mediated cellular responses.

Irradiation of Juvenile, but not Adult, Mammary Gland Increases Stem Cell Self-Renewal and Estrogen Receptor Negative Tumors

“…Together these data suggests that increased stromal TGFβ and epithelial Notch in mice irradiated during puberty mediate a transient increase in symmetric division that increases mammary repopulating cells. Similarly, recent studies using irradiated mammosphere cultures showed that p21 mediates stem cell resistance to p53‐dependent apoptosis and, interestingly, p21 is a direct target of TGFβ signaling . Increased mammary stem cells and the subsequent development of aggressive, ER‐negative breast cancer, which are functionally linked by the cell‐of‐origin hypothesis , are highly correlated in our murine models.…”

Erythropoietin Signaling Regulates Heme Biosynthesis

“…This is because early studies failed to detect changes in cAMP levels despite its stimulatory effect on iron incorporation during RBC maturation that is likely mediated by the synergistic effects of CREB on STAT5 transcription (Boer et al, 2002(Boer et al, , 2003Gidari et al, 1971;Schooley and Mahlmann, 1975). However, recent evidence indicates that PKAc activation is much more complex involving direct protein-protein interactions with other cell signaling regulators and feedback mechanisms independent of cAMP (Taylor et al, 2012;Wong and Scott, 2004;Yang et al, 2013Yang et al, , 1995Zakhary et al, 2000). Thus, we next asked whether PKAc interacts with proteins in the EPOR/JAK2/STAT5 signaling pathway, leading to its activation.…”

A sinalização de TGF-β envolvida na expressão de CD39 em células T reguladoras está associada com a eficácia terapêutica do metotrexato na artrite reumatóide

“…However, the affinity of SMADs to the DNA in SBE regions is low, and then SMADs can act in cooperation with other transcription factors, including CREB, promoting transcription (25,47). Additionally, CREB phosphorylation can be mediated after activation of PKA by TGFBRI or SMADs activity, such as SMAD4, which interacts with the regulatory domain of PKA (25,40,48,49). Taking into account, we found that CREB activation is essential for mediating induction of CD39 expression by TGF-β.…”

“…As SMADs são transdutores de sinais intracelulares que ao serem ativados translocam para o núcleo, onde induzem diretamente ou interagindo com outros fatores de transcrição, como CREB, a transcrição de seus genes alvo (Warner et al, 2003;Yan et al, 2009 (Moustakas & Heldin, 2005;Warner et al, 2003;Yang et al, 2013;Kramer et al, 1991). Por outro lado, outras quinases também podem fosforilar e ativar CREB, como p38, Erk e PI3K/AKT (Steven & Seliger, 2015;.…”

“…Posteriormente da avaliação da capacidade de diferenciação celular determinada pela expressão de FoxP3, investigamos se estas células Tregs diferenciadas in vitro apresentavam também um aumento da expressão de CD39 na superfície, visto que já é bem descrito na literatura que células Tregs, principalmente nTregs, possuem uma elevada expressão tanto de CD39 quanto de CD73 na superfície quando comparadas aos demais subtipos celulares . Ainda, avaliamos se as diferentes concentrações de TGF-β utilizadas durante a diferenciação celular poderiam influenciar os níveis de expressão de CD39 em Além da fosforilação das SMADs como consequência da ligação do TGF-β aos receptores TGFBRII/TGFBRI, é descrito na literatura que o TGFBRI também pode ativar PKA (Kramer et al, 1991;Warner et al, 2003a;Moustakas & Heldin, 2005;Yang et al, 2013).…”