SMAD versus Non-SMAD Signaling Is Determined by Lateral Mobility of Bone Morphogenetic Protein (BMP) Receptors

Guzman, Asja; Zelman-Femiak, Monika; Boergermann, Jan H.; Paschkowsky, Sandra; Kreuzaler, Peter; Fratzl, Peter; Harms, Gregory S.; Knaus, Petra

doi:10.1074/jbc.m112.387639

Cited by 56 publications

(52 citation statements)

References 47 publications

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“…Such clustering is consistent with either the aggregation of plasmamembrane-localized AMHRII or the existence of AMHRII-rich membrane subcompartments. Ligand activation of downstream signaling pathways has been shown to be influenced by the localization of TGFb receptors to cholesterol-rich domains (Shapira et al, 2014) and by the degree of lateral mobility or confinement of BMP receptors into membrane microdomains (Guzman et al, 2012). Thus, there are likely to be significant consequences of the AMHRII localization pattern that we have elucidated in this study on its signaling output.…”

Section: Discussionmentioning

confidence: 83%

Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II

Hirschhorn

Clemente

Amsalem

et al. 2015

Journal of Cell Science

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The levels and intracellular localization of wild-type transforming growth factor b superfamily (TGFb-SF) receptors are tightly regulated by endocytic trafficking, shedding and degradation. In contrast, a main regulatory mechanism of mutation-bearing receptors involves their intracellular retention. Anti-Mü llerian hormone receptor II (AMHRII, also known as AMHR2) is the type-II receptor for anti-Mü llerian hormone (AMH), a TGFb-SF ligand that mediates Mü llerian duct regression in males. Here, we studied AMHRII processing and identified novel mechanisms of its constitutive negative regulation. Immunoblot analysis revealed that a significant portion of AMHRII was missing most of its extracellular domain (ECD) and, although glycosylated, was unfolded and retained in the endoplasmic reticulum. Exogenous expression of AMHRII, but not of type-II TGF-b receptor (TbRII, also known as TGFR2), resulted in its disulfide-bond-mediated homooligomerization and intracellular retention, and in a decrease in its AMH-binding capacity. At the plasma membrane, AMHRII differed from TbRII, forming high levels of non-covalent homomeric complexes, which exhibited a clustered distribution and restricted lateral mobility. This study identifies novel mechanisms of negative regulation of a type-II TGFb-SF receptor through cleavage, intracellular retention and/or promiscuous disulfide-bond mediated homo-oligomerization.

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Section: Discussionmentioning

confidence: 83%

Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II

Hirschhorn

Clemente

Amsalem

et al. 2015

Journal of Cell Science

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“…Although Foxd1 −/− kidneys are much smaller than wild-type kidneys, proliferation within cap mesenchyme does not differ significantly, indicating that the effect of BMP on progenitor proliferation is unchanged and suggesting that signaling through SMAD1/5 is specifically affected by DCN (Levinson et al, 2005). Factors governing signaling outcomes of BMP receptor activation are incompletely understood, but include receptor complex conformation at the cell surface, which may be strongly influenced by the extracellular environment (Guzman et al, 2012). Future studies of the molecular mechanism by which DCN acts on BMP ligands and receptors will explore the possibility that it does not simply inhibit BMP signaling, but redirects its outcome.…”

Section: Research Articlementioning

confidence: 99%

FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney

et al. 2014

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Forkhead transcription factors are essential for diverse processes in early embryonic development and organogenesis. Foxd1 is required during kidney development and its inactivation results in failure of nephron progenitor cell differentiation. Foxd1 is expressed in interstitial cells adjacent to nephron progenitor cells, suggesting an essential role for the progenitor cell niche in nephrogenesis. To better understand how cortical interstitial cells in general, and FOXD1 in particular, influence the progenitor cell niche, we examined the differentiation states of two progenitor cell subtypes in Foxd1 −/− tissue. We found that although nephron progenitor cells are retained in a primitive CITED1-expressing compartment, cortical interstitial cells prematurely differentiate. To identify pathways regulated by FOXD1, we screened for target genes by comparison of Foxd1 null and wild-type tissues. We found that the gene encoding the small leucine-rich proteoglycan decorin (DCN) is repressed by FOXD1 in cortical interstitial cells, and we show that compound genetic inactivation of Dcn partially rescues the failure of progenitor cell differentiation in the Foxd1 null. We demonstrate that DCN antagonizes BMP/SMAD signaling, which is required for the transition of CITED1-expressing nephron progenitor cells to a state that is primed for WNT-induced epithelial differentiation. On the basis of these studies, we propose a mechanism for progenitor cell retention in the Foxd1 null in which misexpressed DCN produced by prematurely differentiated interstitial cells accumulates in the extracellular matrix, inhibiting BMP7-mediated transition of nephron progenitor cells to a compartment in which they can respond to epithelial induction signals.

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“…The bone morphogenetic protein (BMP) receptors (BMPRs) are transmembrane proteins and belong to the family of serine/threonine kinases that comprises BMPR type I and II. The confinement in lateral mobility and accumulation of signaling receptors in microdomains at the cell membrane is crucial not only for binding to the ligand, but also for activation of signaling cascades [5,6]. Additionally, the different modes of receptor oligomerization dictate the downstream signaling pathways and the resulting transcriptional responses [7,8].…”

Section: Introductionmentioning

confidence: 99%

Challenges in imaging cell surface receptor clusters

Medda

Giske

Cavalcanti‐Adam

2016

Optics and Lasers in Engineering

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SMAD versus Non-SMAD Signaling Is Determined by Lateral Mobility of Bone Morphogenetic Protein (BMP) Receptors

Cited by 56 publications

References 47 publications

Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II

Constitutive negative regulation in the processing of the anti-Müllerian hormone receptor II

FOXD1 promotes nephron progenitor differentiation by repressing decorin in the embryonic kidney

Challenges in imaging cell surface receptor clusters

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