Src transduces signaling via growth hormone (GH)-activated GH receptor (GHR) tyrosine-phosphorylating GHR and STAT5 in human leukemia cells

Manabe, Noriko; Kubota, Yoshihiro; Kitanaka, Akira; Ohnìshì, H.; Taminato, Tomohiko; Tanaka, Terukazu

doi:10.1016/j.leukres.2006.03.024

Cited by 18 publications

(23 citation statements)

References 35 publications

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“…SFK binding to GHR does not appear to require a tyrosine residue for binding, since the mutation Y314A (in 389tr) did not affect GHR and Lyn binding but in fact increased the GHR expression compared to 389tr. An earlier study by Manabe et al have reported that treatment of F-36P human leukemia cells with a Src inhibitor resulted in reduced GHR phosphorylation to the same extent as that of Jak2 inhibition (Manabe et al, 2006). However, with barely detectable levels of endogenous receptor phosphorylation evident from GHR immunoprecipitation, this study failed to determine subtle differences between Src and Jak2-mediated GHR phosphorylation.…”

Section: Based On the Co-ip Results The Lyn Binding Region On Human Gmentioning

confidence: 70%

“…However, with barely detectable levels of endogenous receptor phosphorylation evident from GHR immunoprecipitation, this study failed to determine subtle differences between Src and Jak2-mediated GHR phosphorylation. In addition, the level of tyrosine phosphorylation of GHR in COS-7 cells co-transfected with WT-Src was shown to be of a similar extent when Jak2 was transfected (Manabe et al, 2006). This study however failed to consider that the level of endogenous Jak2 in COS-7 cells would be enough to phosphorylate GHR independent of exogenous Src.…”

Section: Based On the Co-ip Results The Lyn Binding Region On Human Gmentioning

confidence: 78%

“…Earlier study in F-36P leukemia cells has shown Src depletion using siRNA did not affect Jak2 expression or its tyrosine phosphorylation after GH stimulation although GH-mediated STAT5 activation was shown to be reduced in the absence of Src (Manabe et al, 2006). The same study also reported that when WT GHR, Jak2 and Src were co-transfected together, Jak2 and Src coimmunoprecipitated with GHR and this association was seen when non-catalytic Src mutants were used, indicating that Src association with GHR does not require its tyrosine kinase activity (Manabe et al, 2006).…”

Section: An Interesting Observation Made By Chin Et Al Has Been the mentioning

confidence: 87%

“…This has been supported by in vitro demonstration of Jak2-independent Src activation (Manabe et al, 2006;Zhu et al, 2002). Zhu et al provide evidence using both pharmacological inhibitors and kinase inactive proteins in NIH-3T3 cells that tyrosine kinase…”

Section: Jak2-independent Signalling Src Family Kinase Activationmentioning

confidence: 92%

“…The existence of SFK-mediated signalling by GHR in vivo has been demonstrated in targeted Box-1 mutated mouse model (complete abrogation of GHR-mediated Jak2/STAT signalling) and transcripts resulting from Jak-independent Src activation were reported (Barclay et al, 2010). Manabe et al have shown that Src can bind and phosphorylate GHR in F-36P human leukemia cells (Manabe et al, 2006). They reported treatment of cells with Src inhibitors and anti-sense oligonucleotides decreased STAT5 activity, which was independent of Jak2.…”

Section: Jak2-independent Signalling Src Family Kinase Activationmentioning

confidence: 98%

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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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Section: Based On the Co-ip Results The Lyn Binding Region On Human Gmentioning

confidence: 70%

Section: Based On the Co-ip Results The Lyn Binding Region On Human Gmentioning

confidence: 78%

Section: An Interesting Observation Made By Chin Et Al Has Been the mentioning

confidence: 87%

Section: Jak2-independent Signalling Src Family Kinase Activationmentioning

confidence: 92%

Section: Jak2-independent Signalling Src Family Kinase Activationmentioning

confidence: 98%

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The growth hormone receptor mediated oncogenesis

Chhabra¹

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Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cells

Yang

Chien

et al. 2008

J Biochem & Molecular Tox

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N'-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (IQDMA), an indoloquinoline derivative, synthesized in our laboratory, has been demonstrated to be an effective antitumor agent in human leukemia cells. In the present study, treatment with IQDMA inhibited phosphorylation of epidermal growth factor receptor (EGFR), Src, Bcr-Abl, and Janus-activated kinase (JAK2) in a time-dependent manner. IQDMA also degraded JAK2 protein. Moreover, signal transducer and activator of transcription 5 (STAT5) signaling were also blocked by IQDMA. However, IQDMA did not inhibit other oncogenic and tumor survival pathways such as those mediated by Akt and extracellular signal-regulated kinase 1/2. Furthermore, IQDMA upregulated the expression of p21 and p27 and downregulated the expression of cyclin D1, myeloid cell leukemia-1(Mcl-1), Bcl-X(L), and vascular endothelial growth factor (VEGF). Taken together, these results indicate that IQDMA causes significant induction of apoptosis in K562 cells via downregulation of EGFR, Src, Bcr-Abl, JAK2, and STAT5 signaling and modulation of p21, p27, cyclin D1, Mcl-1, Bcl-X(L), and VEGF proteins. Thus, IQDMA appears to be a potential therapeutic agent for treating leukemia K562 cells.

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Recent advances in growth hormone signaling

Lanning

Carter‐Su

2006

Rev Endocr Metab Disord

209

163

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Growth hormone (GH) is a major regulatory factor for overall body growth as evidenced by the height extremes in people with abnormal circulating GH levels or GH receptor (GHR) disruptions. GH also affects metabolism, cardiac and immune function, mental agility and aging. Currently, GH is being used therapeutically for a variety of clinical conditions including promotion of growth in short statured children, treatment of adults with GH deficiency and HIV-associated wasting. To help reveal previous unrecognized functions of GH, better understand the known functions of GH, and avoid adverse consequences that are often associated with exogenous GH administration, careful delineation of the molecular mechanisms whereby GH induces its diverse effects is needed. GH is a peptide hormone that is secreted into the circulation by the anterior pituitary and acts upon various target tissues expressing GHR. GH binding of GHR activates the tyrosine kinase Janus kinase 2 (JAK2), thus initiating a multitude of signaling cascades that result in a variety of biological responses including cellular proliferation, differentiation and migration, prevention of apoptosis, cytoskeletal reorganization and regulation of metabolic pathways. A number of signaling proteins and pathways activated by GH have been identified, including JAKs, signal transducers and activators of transcription (Stats), the mitogen activated protein kinase (MAPK) pathway, and the phosphatidylinositol 3'-kinase (PI3K) pathway. Although these signal transduction pathways have been well characterized, the manner by which GH activates these pathways, the downstream signals induced by these pathways, and the cross-talk with other pathways are not completely understood. Recent findings have added vital information to our understanding of these downstream signals induced by GH and mechanisms that terminate GH signaling, and identified new GH signaling proteins and pathways. This review will highlight some of these findings, many of which are unexpected and some of which challenge previously held beliefs about the mechanisms of GH signaling.

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Src transduces signaling via growth hormone (GH)-activated GH receptor (GHR) tyrosine-phosphorylating GHR and STAT5 in human leukemia cells

Cited by 18 publications

References 35 publications

The growth hormone receptor mediated oncogenesis

The growth hormone receptor mediated oncogenesis

Novel indoloquinoline derivative, IQDMA, inhibits STAT5 signaling associated with apoptosis in K562 cells

Recent advances in growth hormone signaling

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