βTrCP interacts with the ubiquitin-dependent endocytosis motif of the GH receptor in an unconventional manner

Almeida, Ana Carolina da Veiga Rodarte de; Hocking, Henry G.; Boelens, Rolf; Strous, Ger J.; Rossum, Agnes G.S.H. van

doi:10.1042/bj20121843

Cited by 7 publications

(4 citation statements)

References 49 publications

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“…These GHR-containing early endosomes are later fused to the lysosomes leading to GHR degradation [24]. In addition to SOCS2, the ubiquitin ligase β-TRCP has also been shown to mediate GHR ubiquitination and internalization with the key difference that this process is not GH dependent and the mechanism seems to act independently from SOCS2 [25]. Therefore, the current evidence would suggest that GHR membrane content is controlled by ubiquitin driven endocytosis [18].…”

Section: Socs2 Mediates Ghr Turnovermentioning

confidence: 85%

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Fernández-Pérez¹,

Flores‐Morales²,

Guerra³

et al. 2016

Restricted Growth - Clinical, Genetic and Molecular Aspects

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Growth hormone (GH) is a critical regulator of linear body growth during childhood but continues to have important metabolic actions throughout life. The GH receptor (GHR) is ubiquitously expressed, and deficiency of GHR signaling causes a dramatic impact on normal physiology during somatic development, adulthood, and aging. GHR belongs to a family of receptors without intrinsic kinase activity. However, GH binding to homodimers of GHR results in a conformational change in the receptors and the associated tyrosine kinase Janus kinase 2 (JAK2) molecules. Activated JAK2 phosphorylates the GHR cytoplasmic domain on tyrosine residues, and subsequent JAK2-dependent and JAK2-independent intracellular signal transduction pathways evoke cell responses including changes in gene transcription, proliferation, cytoskeletal reorganization, and lipid and glucose metabolism. JAK2 phosphorylates STAT5b, which is a key transcription factor in GH regulation of target genes associated with body growth, intermediate metabolism, and gender dimorphism; although STAT1, 3, and 5a have also been shown to be recruited by the GHR. In addition, many transcripts are regulated independently of STAT5b as a result of GHR activation of Src, ERK, and PI3K-mTOR signaling pathways. The analysis of molecular mechanisms involved in inactivation of GHR-dependent signaling pathway is also imperative for understanding GH physiology. This is clearly illustrated in the case of hepatic GHR-JAK2-STAT5b activation where signal duration regulates gender differences in liver gene expression. An early step in the termination of GH-dependent signaling is removal of GHRs by endocytosis and ubiquitination. The level of ubiquitin ligase SOCS2 is constitutively low, but its expression is rapidly induced by GH. SOCS2 binding to GHR complex promotes their ubiquitination and subsequent proteasomal degradation, contributing to the termination of the GH intracellular signaling. Clinically relevant, SOCS2 is a key negative regulator of GH-dependent body growth and lipid and glucose homeostasis. Furthermore, several cytokines, growth factors, xenobiotics, and sex hormones can regulate SOCS2 protein level, which provides a mechanism for cross-talking where multiple factors can regulate GHR signaling during somatic development. A better understanding of this complex regulation in physiological and pathological states will contribute to prevent health damage and improve clinical management of patients with growth and metabolic disorders.

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Section: Socs2 Mediates Ghr Turnovermentioning

confidence: 85%

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Fernández-Pérez¹,

Flores‐Morales²,

Guerra³

et al. 2016

Restricted Growth - Clinical, Genetic and Molecular Aspects

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“…This role is carried out by the UbE motif, important for both steady state and GH-induced endocytosis (42,92). NMR experiments demonstrated that the UbE motif is essentially unstructured, and, together with functional mapping of the UbE and bTrCP revealed a unique interaction model of bTrCP with GHR-UbE (178). Since the regulation of bTrCPsubstrates interactions involves serine phosphorylation, we evaluated the potential role of the UbE serine phosphorylation (S341) as a modulator of UbE-bTrCP interaction.…”

Section: Role Of Scf Trcp1 In Ghr Endocytosismentioning

confidence: 99%

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases

et al. 2020

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“…In the case of GHR however β-TrCP has been shown to bind to the highly conserved but unstructured DSWVEFIELD (UbE) motif and the 30 residue downstream DSGRTS motif . The β-TrCP binding to the UbE motif although specific is unconventional and with a lower affinity than the phosphorylated DSGxxS motif (da Silva Almeida et al, 2013). Using the F327A (UbE mutant), a DAGxxA mutant and double mutants it was shown that β-TrCP acts mainly via UbE motif in GH-induced conditions, whereas both the motifs supported ubiquitination in the basal conditions contributing to GHR homeostasis in the cells .…”

Section: Ubiquitin-dependent Ghr Internalisationmentioning

confidence: 99%

“…One such unstructured motif is the Ubiquitin-dependent Endocytosis (UbE) comprised of residues 322 DSWVEFIELD 331 in the Box2 region (Govers et al, 1999;da Silva Almeida et al, 2013). Finally, the ICD contains di-leucine motifs and a DSGxxS degradon discussed in detail later.…”

Section: Growth Hormone Receptormentioning

confidence: 99%

The growth hormone receptor mediated oncogenesis

Chhabra¹

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Growth hormone (GH) is a major regulator of postnatal growth, cellular proliferation and differentiation, as well as of metabolism. All actions of GH are mediated via its cognate Growth Hormone Receptor (GHR). It is now clear that the role of GH extends well beyond the conventional notions of longitudinal growth and childhood development. A substantial body of evidence supports a role for the GH/IGF-1 axis in cancer incidence and progression in animals and humans and because of widespread clinical application of GH, there has been considerable interest in the mechanism of activation of its receptor. It was originally thought that GH initiated its actions by sequentially binding two GHR monomers, resulting in receptor dimerisation and initiation of intracellular signalling cascades, including Jak/STAT and MAPK pathways. However, recent evidence by our group and others has indicated that the GHR is constitutively dimerised, and that dimerisation alone is not sufficient for GHR activation.To this end the main objective of this thesis was to evaluate the role of GH-mediated signalling via its GHR in mediating oncogenesis. We have taken a multi-disciplinary approach by first determining how the GHR is activated via its transmembrane domain (TMD) and the nature of its interaction with Src family of tyrosine kinase (Lyn). We have determined the basis of the contrasting actions of autocrine GH from independent publications and sought to evaluate the effect of various constitutively active GHR constructs in cancer promotion in vitro and in vivo by establishing a tissue-specific delivery system (TVA system) for introducing multiple genes in a spatial and temporally controlled manner. We have provided the molecular basis of increased cancer susceptibility of the first reported GHR variant from two independent epidemiological studies. Finally, we have evaluated cancer resistance and anti-aging pathways in various GHR knockin and knockout mice models.In order to determine the role of GHR transmembrane domain (TMD) and upper juxtamembrane domain (JMD) in signalling, cysteine-scanning mutagenesis was employed with truncated and full length receptors in a thiol-free background. Using these GHR constructs and sequentially substituting residues along the GHR JMD and TMD with cysteine we observed a ligandindependent spontaneous dimerisation pattern of upper JMD and TMD residues with evidence for a 'tilt and twist' movement for this region of GHR during activation. By using Cu-o-phenanthroline we were able to show that GHR activation could occur following disulfide bond formation at the upper TMD boundary resulting in constitutive activation. Finally we were able to conclude that GHR activation requires the JMD residues to come in close proximity which results in separation of iii the lower TMD residues and activation. Another outcome of this study was the generation of the first full-length constitutively active receptor.GHR has been shown to activate numerous pathways and one such pathway involves Src Family Kinase (SFK),...

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βTrCP interacts with the ubiquitin-dependent endocytosis motif of the GH receptor in an unconventional manner

Cited by 7 publications

References 49 publications

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Growth Hormone Receptor Signaling Pathways and its Negative Regulation by SOCS2

Growth Hormone Receptor Regulation in Cancer and Chronic Diseases

The growth hormone receptor mediated oncogenesis

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