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Hormonal induction and roles of Disabled-2 in lactation and involution.

Tao W, Moore R, Smith ER, Xu XX - PLoS ONE (2014)

Bottom Line: Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution.However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells.We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center, and Department of Cell Biology, Graduate Program in Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT
Disabled-2 (Dab2) is a widely expressed endocytic adaptor that was first isolated as a 96 KDa phospho-protein, p96, involved in MAPK signal transduction. Dab2 expression is lost in several cancer types including breast cancer, and Dab2 is thought to have a tumor suppressor function. In mammary epithelia, Dab2 was induced upon pregnancy and further elevated during lactation. We constructed mutant mice with a mosaic Dab2 gene deletion to bypass early embryonic lethality and to investigate the roles of Dab2 in mammary physiology. Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution. In primary cultures of mouse mammary epithelial cells, Dab2 proteins were also induced by estrogen, progesterone, and/or prolactin. Dab2 mammary epithelial cells were refractory to growth suppression induced by TGF-beta. However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells. We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

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Schematic illustration of a working model for Dab2 in modulation of TGF-beta pathway.Canonical TGF-beta signaling pathway consists of Smad phosphorylation and mediation of transcriptional regulation, leading to cell death and growth suppression, representing a tumor suppressor activity. The non-canonical route includes the activation of Ras/MAPK pathway as a result of phosphorylation and binding of TGF-beta receptor to Shc and consequently recruitment of Grb2 and Sos. TGF-beta-stimulated activation of Ras/MAPK pathway induces expression of genes involved in cell survival and growth. Dab2 modulates TGF-beta signaling by sequestering Grb2 from Sos, resulting in a reduction of Ras/MAPK activation yet allowing Smad-mediated gene transcription.
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pone-0110737-g008: Schematic illustration of a working model for Dab2 in modulation of TGF-beta pathway.Canonical TGF-beta signaling pathway consists of Smad phosphorylation and mediation of transcriptional regulation, leading to cell death and growth suppression, representing a tumor suppressor activity. The non-canonical route includes the activation of Ras/MAPK pathway as a result of phosphorylation and binding of TGF-beta receptor to Shc and consequently recruitment of Grb2 and Sos. TGF-beta-stimulated activation of Ras/MAPK pathway induces expression of genes involved in cell survival and growth. Dab2 modulates TGF-beta signaling by sequestering Grb2 from Sos, resulting in a reduction of Ras/MAPK activation yet allowing Smad-mediated gene transcription.

Mentions: The current study reports the induction of Dab2 expression and the phenotype of mammary glands in Dab2 conditional knockout mice. Dab2 deficiency delays epithelial cell death and clearance during mammary involution. We have provided data to suggest a working model whereby Dab2 expression is induced during lactation to modulate TGF-beta signaling by suppressing TGF-beta-stimulated MAPK activation. Dab2 retards MAPK activation by competing with Sos for binding to Grb2 and thus ultimately suppresses the signaling pathway (Figure 8).


Hormonal induction and roles of Disabled-2 in lactation and involution.

Tao W, Moore R, Smith ER, Xu XX - PLoS ONE (2014)

Schematic illustration of a working model for Dab2 in modulation of TGF-beta pathway.Canonical TGF-beta signaling pathway consists of Smad phosphorylation and mediation of transcriptional regulation, leading to cell death and growth suppression, representing a tumor suppressor activity. The non-canonical route includes the activation of Ras/MAPK pathway as a result of phosphorylation and binding of TGF-beta receptor to Shc and consequently recruitment of Grb2 and Sos. TGF-beta-stimulated activation of Ras/MAPK pathway induces expression of genes involved in cell survival and growth. Dab2 modulates TGF-beta signaling by sequestering Grb2 from Sos, resulting in a reduction of Ras/MAPK activation yet allowing Smad-mediated gene transcription.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4216001&req=5

pone-0110737-g008: Schematic illustration of a working model for Dab2 in modulation of TGF-beta pathway.Canonical TGF-beta signaling pathway consists of Smad phosphorylation and mediation of transcriptional regulation, leading to cell death and growth suppression, representing a tumor suppressor activity. The non-canonical route includes the activation of Ras/MAPK pathway as a result of phosphorylation and binding of TGF-beta receptor to Shc and consequently recruitment of Grb2 and Sos. TGF-beta-stimulated activation of Ras/MAPK pathway induces expression of genes involved in cell survival and growth. Dab2 modulates TGF-beta signaling by sequestering Grb2 from Sos, resulting in a reduction of Ras/MAPK activation yet allowing Smad-mediated gene transcription.
Mentions: The current study reports the induction of Dab2 expression and the phenotype of mammary glands in Dab2 conditional knockout mice. Dab2 deficiency delays epithelial cell death and clearance during mammary involution. We have provided data to suggest a working model whereby Dab2 expression is induced during lactation to modulate TGF-beta signaling by suppressing TGF-beta-stimulated MAPK activation. Dab2 retards MAPK activation by competing with Sos for binding to Grb2 and thus ultimately suppresses the signaling pathway (Figure 8).

Bottom Line: Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution.However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells.We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

View Article: PubMed Central - PubMed

Affiliation: Sylvester Comprehensive Cancer Center, and Department of Cell Biology, Graduate Program in Molecular Cell and Developmental Biology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.

ABSTRACT
Disabled-2 (Dab2) is a widely expressed endocytic adaptor that was first isolated as a 96 KDa phospho-protein, p96, involved in MAPK signal transduction. Dab2 expression is lost in several cancer types including breast cancer, and Dab2 is thought to have a tumor suppressor function. In mammary epithelia, Dab2 was induced upon pregnancy and further elevated during lactation. We constructed mutant mice with a mosaic Dab2 gene deletion to bypass early embryonic lethality and to investigate the roles of Dab2 in mammary physiology. Loss of Dab2 had subtle effects on lactation, but Dab2-deficient mammary glands showed a strikingly delayed cell clearance during involution. In primary cultures of mouse mammary epithelial cells, Dab2 proteins were also induced by estrogen, progesterone, and/or prolactin. Dab2 mammary epithelial cells were refractory to growth suppression induced by TGF-beta. However, Dab2 deletion did not affect Smad2 phosphorylation; rather TGF-beta-stimulated MAPK activation was enhanced in Dab2-deficient cells. We conclude that Dab2 expression is induced by hormones and Dab2 plays a role in modulating TGF-beta signaling to enhance apoptotic clearance of mammary epithelial cells during involution.

Show MeSH
Related in: MedlinePlus