Genetic and biochemical analysis of TGFβ signal transduction

Padgett, Richard W.; Savage, Cathy; Das, Pradeep

doi:10.1016/s1359-6101(96)00050-0

Cited by 25 publications

(18 citation statements)

References 65 publications

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“…Although there are no yeast TGF-␤s, homologs have been identified in primitive metazoans, including Caenorhabditis elegans and Drosophila (2)(3)(4). With the exception of only glial-derived neurotrophic factor, these ligands signal through heterotetrameric pairs of serine-threonine kinase receptors.…”

mentioning

confidence: 99%

Sorting Nexin 6, a Novel SNX, Interacts with the Transforming Growth Factor-β Family of Receptor Serine-Threonine Kinases

Parks¹,

Frank²,

Huff³

et al. 2001

Journal of Biological Chemistry

127

114

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Sorting nexins (SNX) comprise a family of proteins with homology to several yeast proteins, including Vps5p and Mvp1p, that are required for the sorting of proteins to the yeast vacuole. Human SNX1, -2, and -4 have been proposed to play a role in receptor trafficking and have been shown to bind to several receptor tyrosine kinases, including receptors for epidermal growth factor, platelet-derived growth factor, and insulin as well as the long form of the leptin receptor, a glycoprotein 130-associated receptor. We now describe a novel member of this family, SNX6, which interacts with members of the transforming growth factor-␤ family of receptor serine-threonine kinases. These receptors belong to two classes: type II receptors that bind ligand, and type I receptors that are subsequently recruited to transduce the signal. Of the type II receptors, SNX6 was found to interact strongly with ActRIIB and more moderately with wild type and kinase-defective mutants of T␤RII. Of the type I receptors, SNX6 was found to interact only with inactivated T␤RI. SNXs 1-4 also interacted with the transforming growth factor-␤ receptor family, showing different receptor preferences. Conversely, SNX6 behaved similarly to the other SNX proteins in its interactions with receptor tyrosine kinases. Strong heteromeric interactions were also seen among SNX1, -2, -4, and -6, suggesting the formation in vivo of oligomeric complexes. These findings are the first evidence for the association of the SNX family of molecules with receptor serine-threonine kinases.The transforming growth factor-␤ (TGF-␤) 1 family includes a large number of peptides, including the TGF-␤s themselves, activin/inhibin, the bone morphogenetic proteins (BMPs), the growth and differentiation factors (GDFs), glial-derived neurotrophic factor, and Mü llerian inhibitory substance (1). Although there are no yeast TGF-␤s, homologs have been identified in primitive metazoans, including Caenorhabditis elegans and Drosophila (2-4). With the exception of only glial-derived neurotrophic factor, these ligands signal through heterotetrameric pairs of serine-threonine kinase receptors. Ligand first interacts with a type II receptor, which, following ligand binding, recruits a type I receptor (5). The type II receptors are constitutively active kinases, catalyzing phosphorylation both of themselves in an autocatalytic reaction and of the recruited type I receptor (6). Once bound to ligand and phosphorylated by the type II receptor, the type I receptor then transduces the signal to the intracellular signaling intermediates, including the recently described family of Smad proteins (7-13). In general, one or two closely related type I and one or two closely related type II receptors are utilized by each class of ligand. For example, TGF-␤1 and TGF-␤3 bind to the type II TGF-␤ receptor (T␤RII), with subsequent recruitment of the type I TGF-␤ receptor (T␤RI/ALK5 (activin-like kinase 5)) (6). Similarly, activin binds to either ActRII or ActRIIB, with activin type IB receptor (ALK4) or possi...

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mentioning

confidence: 99%

Sorting Nexin 6, a Novel SNX, Interacts with the Transforming Growth Factor-β Family of Receptor Serine-Threonine Kinases

Parks¹,

Frank²,

Huff³

et al. 2001

Journal of Biological Chemistry

127

114

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“…The activated serine domain then phosphorylates a receptor-regulated SMAD (R-SMAD) protein. The R-SMAD binds with a coSMAD, and this complex then enters the nucleus to bind transcription promoters and cofactors leading to transcription of downstream effectors (Padgett et al, 1997;Wrana, 1998). BMPs lead to transcription of genes involved in neurogenesis, as well as osteogenesis, while TGF␤ proteins lead to transcription of genes involved in immunosuppression, as well as cellular apoptosis, among other processes.…”

Section: Tgf〉/bmp Pathwaymentioning

confidence: 99%

Developmental signaling pathways in brain tumor‐derived stem‐like cells

Clark

Treisman

Ebben

et al. 2007

Developmental Dynamics

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“…Members of this family have been characterized as modulators of cell proliferation and differentiation as well as critical regulators of developmental processes in vertebrate and invertebrate species (reviewed in Kingsley, 1994a;Hogan, 1996a,b;Padgett et at., 1997). From studies of the TGF-f system, subsequently extended to the activins and BMPs, it has been demonstrated that these cytokines signal through transmembrane serine/threonine kinase receptors.…”

Section: Introductionmentioning

confidence: 99%

BMP Receptors in Limb and Tooth Formation

Cheifetz

1999

Critical Reviews in Oral Biology & Medicine

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Members of the TGF-3 superfamily signal through receptor complexes comprised of type I and type 11 receptors.These receptors, which are serine/threonine kinases, form two new classes of transmembrane receptor kinases. The activity of both of the kinases is necessary for signal transduction in response to ligand binding. Bone morphogenetic proteins (BMPs), which are members of the TGF-:3 superfamily, bind to multiple type I and type 11 receptors. There is growing evidence to support the hypothesis that the BMP receptors are differentially regulated during development and that they have both unique and overlapping functions. Thus, the nature and distribution of the BMP receptors, which are reviewed here in the context of the development of limbs and teeth, appear to be critical in the control of the diverse activities of BMPs.

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Genetic and biochemical analysis of TGFβ signal transduction

Cited by 25 publications

References 65 publications

Sorting Nexin 6, a Novel SNX, Interacts with the Transforming Growth Factor-β Family of Receptor Serine-Threonine Kinases

Sorting Nexin 6, a Novel SNX, Interacts with the Transforming Growth Factor-β Family of Receptor Serine-Threonine Kinases

Developmental signaling pathways in brain tumor‐derived stem‐like cells

BMP Receptors in Limb and Tooth Formation

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