Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor‐β type II receptor family

He, Wei; Gustafson, Michael L.; Hirobe, Seiichi; Donahoe, Patricia K.

doi:10.1002/aja.1001960207

Cited by 164 publications

(84 citation statements)

References 47 publications

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“…Thus, active TGF-␤-like ligands must exist within the follicle to drive nuclear accumulation of Smad2. Notably, granulosa cells actively secrete activin A, and they express cognate activin receptors (22,23,26), suggesting autocrine signaling in ovarian cells. Activin is therefore a possible candidate for an autocrine ligand that triggers activation and nuclear translocation of Smad2.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence suggesting that activins are not only endocrine regulators of FSH availability but also potent effectors of autocrine or paracrine intraovarian signaling. Activin receptors and downstream Smad proteins are present in rat ovaries (22)(23)(24)(25)(26), and activins apparently play important roles in regulation of folliculogenesis and follicular function (27)(28)(29)(30). However, the knowledge about granulosa cells and how they respond to Smad signaling and its regulation is still rudimentary.…”

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confidence: 99%

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Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

Schmierer

Schuster

Shkumatava

et al. 2003

Journal of Biological Chemistry

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Activin A signaling is an important regulator of ovarian granulosa cell function. The cytosolic signal transducer Smad2 is most highly expressed in chicken granulosa cells (cGC) of preovulatory follicles. Moreover, Smad2 shows predominant nuclear localization in freshly isolated cGC, indicating active Smad signaling in vivo. Primary cGC cultured in vitro require activin A to sustain high Smad2 levels, which otherwise drop dramatically in the absence of activin A. This activin A-dependent Smad2 expression is abrogated by protein kinase A (PKA) inhibitors, suggesting a role for PKA in activin signaling. In the absence of activin A, strong PKA activators such as follicle-stimulating hormone (FSH) and 8-bromo-cyclic AMP fail to elicit Smad2 induction. However, FSH and 8-bromo-cyclic AMP boost activin A-dependent Smad2 up-regulation, giving rise to Smad2 levels similar to expression in vivo levels. Interestingly, the effect is specific for Smad2, since expression of the structurally and functionally closely related Smad3 remains entirely unaffected. Hence, activin A induces Smad2, but not Smad3, to high levels requiring PKA activation. Since Smad2 and Smad3 target distinct yet overlapping sets of TGF-␤/activin-responsive genes, the selective Smad2 induction by FSH/activin A could allow FSH to efficiently modulate the transcriptional readout of activin A signaling in avian granulosa cells.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

Schmierer

Schuster

Shkumatava

et al. 2003

Journal of Biological Chemistry

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“…The type I receptor mutant, T202D, was derived from the rat R4 type I TGF-␤ receptor (23) and contained a mutation of threonine 202 to an aspartic acid, resulting in a constitutively active receptor kinase that signaled in a ligand-independent manner 3 similar to the analogous mutation in the human type I receptor T␤RI, T204D (24).…”

Section: Methodsmentioning

confidence: 99%

The Type II Transforming Growth Factor (TGF)-β Receptor-interacting Protein TRIP-1 Acts as a Modulator of the TGF-β Response

Choy

Derynck

1998

Journal of Biological Chemistry

116

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The transforming growth factor-␤ (TGF-␤) receptor interacting protein TRIP-1 was originally identified as a WD40 repeat-containing protein that has the ability to associate with the TGF-␤ type II receptor and is phosphorylated by it (1). However, its function was not known. We now show that TRIP-1 expression represses the ability of TGF-␤ to induce transcription from the plasminogen activator inhibitor-1 promoter, a common reporter of the TGF-␤-induced gene expression response, but does not affect the ability of TGF-␤ to inhibit cyclin A transcription. TRIP-1 can also inhibit the plasminogen activator inhibitor-1 expression induced by Smads as well as activated TGF-␤ type I receptors. Its inhibitory effect is exerted by a combination of receptordependent and receptor-independent mechanisms. Deletion mutational analysis revealed that two distinct regions, which do not contain recognizable WD40 repeats, are required for the ability of TRIP-1 to inhibit the gene expression response. Expression of other segments of TRIP-1 increased the TGF-␤-induced gene expression response and therefore may exert a dominant negative phenotype. We conclude that TRIP-1 acts as a modulator of the TGF-␤ response. Transforming growth factor-␤ (TGF-␤)1 is the prototype member of a superfamily of growth factors, which have many roles in growth regulation, wound healing, immunity, and development. Most notably, TGF-␤ is a potent growth inhibitor for many cell types and induces a variety of extracellular matrix proteins and adhesion receptors (2). The current model for TGF-␤ signaling invokes the binding of ligand to the type II TGF-␤ receptor, which results in the recruitment, phosphorylation, and concomitant activation of type I TGF-␤ receptors. The activated type I receptor then phosphorylates Smad2 or Smad3, which is then released from the receptor and forms a complex with Smad4. This complex then translocates to the nucleus where it interacts with transcription factors and regulates gene expression (3).Although Smads clearly act as effectors of TGF-␤ receptor signaling, several lines of evidence indicate that other factors are probably involved in TGF-␤ signal transduction. The ability of a dominant negative type II receptor to inhibit TGF-␤-mediated growth inhibition but not extracellular matrix production suggests that the pathways leading to these effects of TGF-␤ are distinct and separable (4) and may be differentially regulated via quantitatively different thresholds of signaling (5). Consistent with this notion, specific residues on the type I (6) or type II (7) receptor have been identified that are dispensable for TGF-␤ stimulation of extracellular matrix production but required for the antimitogenic effect. The Smads have been found to mediate both the extracellular matrix and the antimitogenic signaling pathways (3,8,9), and no evidence yet presented has indicated a role for Smads in differentially modulating distinct TGF-␤ signaling pathways. Thus, although the basis for distinction between these pathways is not well underst...

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“…Two type II receptors, ActRIIA and ActRIIB, are known as activin receptors on the basis of their high affinity for activin (Mathews and Vale 1991;Attisano et al 1992). One of the type I receptors, ActRIB (also known as ALK4 or R2) (He et al 1993;ten Dijke et al 1993), can form heteromeric complexes with either type II activin receptor to specifically mediate activin signaling (ten Dijke et al 1993(ten Dijke et al , 1994aCarcamo et al 1994). The signal transduction mechanism for activin has been extensively studied and shown to be similar to that of TGF␤ signaling (for review, see Derynck and Zhang 1996;Massagué 1996).…”

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confidence: 99%

The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse

Nomura²,

Simpson

et al. 1998

Genes & Development

200

124

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ActRIB is a type I transmembrane serine/threonine kinase receptor that has been shown to form heteromeric complexes with the type II activin receptors to mediate activin signal. To investigate the function of ActRIB in mammalian development, we generated ActRIB-deficient ES cell lines and mice by gene targeting. Analysis of the ActRIB −/− embryos showed that the epiblast and the extraembryonic ectoderm were disorganized, resulting in disruption and developmental arrest of the egg cylinder before gastrulation. To assess the function of ActRIB in mesoderm formation and gastrulation, chimera analysis was conducted. We found that ActRIB −/− ES cells injected into wild-type blastocysts were able to contribute to the mesoderm in chimeric embryos, suggesting that ActRIB is not required for mesoderm formation. Primitive streak formation, however, was impaired in chimeras when ActRIB −/− cells contributed highly to the epiblast. Further, chimeras generated by injection of wild-type ES cells into ActRIB −/− blastocysts formed relatively normal extraembryonic tissues, but the embryo proper developed poorly probably resulting from severe gastrulation defect. These results provide genetic evidence that ActRIB functions in both epiblast and extraembryonic cells to mediate signals that are required for egg cylinder organization and gastrulation.

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Developmental expression of four novel serine/threonine kinase receptors homologous to the activin/transforming growth factor‐β type II receptor family

Cited by 164 publications

References 47 publications

Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

Activin A Signaling Induces Smad2, but Not Smad3, Requiring Protein Kinase A Activity in Granulosa Cells from the Avian Ovary

The Type II Transforming Growth Factor (TGF)-β Receptor-interacting Protein TRIP-1 Acts as a Modulator of the TGF-β Response

The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse

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