Identification of a truncated kinase suppressor of Ras 2 mRNA in sperm

Guo, Lili; Volle, Deanna J.; Lewis, Robert E.

doi:10.1016/j.fob.2014.04.004

Cited by 7 publications

(9 citation statements)

References 28 publications

(48 reference statements)

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“…However, KSR2 mRNA expression in white adipose tissue is exceedingly low (Costanzo‐Garvey et al. ; Guo et al ), suggesting that, in vivo, noncell autonomous effects of KSR2 on lipid metabolism predominate. Data here show that defects in AICAR tolerance, which presumably reflect the activation of AMPK in vivo, are not evident prior to increased adiposity in ksr2 −/− mice at 7 weeks of age (Fig.…”

Section: Discussionmentioning

confidence: 99%

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2^−
/− mice

et al. 2014

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Disruption of KSR2 in humans and mice decreases metabolic rate and induces obesity, coincident with dysregulation of glucose homeostasis. Relative to wild‐type mice, ksr2−/− mice are small prior to weaning with normal glucose tolerance at 6 weeks of age, but demonstrate excess adiposity by 9 weeks and glucose intolerance by 12–14 weeks. Defects in AICAR tolerance, a measure of whole‐body AMPK activation, are detectable only when ksr2−/− mice are obese. Food restriction prevents the obesity of adult ksr2−/− mice and normalizes glucose and AICAR sensitivity. Obesity and glucose intolerance return when ad lib feeding is restored to the diet‐restricted mice, indicating that glucose dysregulation is secondary to obesity in ksr2−/− mice. The phenotype of C57BL/6 ksr2−/− mice, including obesity and obesity‐related dysregulation of glucose homeostasis, recapitulates that of humans with KSR2 mutations, demonstrating the applicability of the C57BL/6 ksr2−/− mouse model to the study of the pathogenesis of human disease. These data implicate KSR2 as a physiological regulator of glucose metabolism during development affecting energy sensing, insulin signaling, and lipid storage, and demonstrate the value of the C57BL/6 ksr2−/− mouse model as a unique and relevant model system in which to develop and test therapeutic targets for the prevention and treatment of obesity, type 2 diabetes, and obesity‐related metabolic disorders.

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Section: Discussionmentioning

confidence: 99%

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2^−
/− mice

et al. 2014

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“…In contrast, ksr2 -/-mice were described to have problems to obtain offspring. This difficulty could be due to the fact that in ksr2 -/-male mice have a reduced sex drive, an infrequent copulation (Guo et al 2014). We observed that the fertility in male ksr2 -/-is strongly impaired and is correlated to a reduced coupling ability and also to altered spermatogenesis.…”

Section: Discussionmentioning

confidence: 72%

“…The latter reason was explored in the present study. It is noteworthy that a translatable truncated KSR2 mRNA has been recently identified in mouse testes and mature sperm (Guo et al 2014), suggesting that this variant of KSR2 may play a unique role in male reproduction.…”

Section: Discussionmentioning

confidence: 99%

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Ultrastructural study of spermatogenesis in KSR2 deficient mice

et al. 2015

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The aim of this study was to investigate the spermatogenesis in ksr2(-/-) mice. Spermatogenesis in 12-15 week-old C57BL/6 wt and ksr2(-/-) mice was observed in testicular tissue and epididymal sperm by light and transmission electron microscopy. The reproductive capacity of male ksr2(-/-) mice was strongly impaired. Concentration, morphology and motility of epididymal spermatozoa were altered in ksr2(-/-) mice. In seminiferous tubules from ksr2(-/-) mice, all stages of spermatogenetic process were represented; spermatids displayed defects concerning nuclear and acrosomal shape and periaxonemal structures of the tail; detached head and spermatozoa with an altered head-tail connection were observed; the interstitial tissue was severely disorganized, the Leydig cells have lost their connections. TEM analysis of epididymal spermatozoa confirmed the presence of such kind of alterations. We reported, for the first time, an ultrastructural study of ksr2(-/-) mice spermatogenesis. Remarkable findings regard the altered spermiogenetic process concomitant with a severe disorganization of interstitial tissue. Further studies are needed to assess the ksr2(-/-) mice hormonal status, focussing on testosterone levels since the interstitial tissue, where the Leydig cells reside, was compromised.

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“…B-KSR1 is a splice variant of murine KSR1 that is preferentially expressed in neural tissues that largely acts like KSR1 in regards to Raf/MEK/ERK interactions and signaling regulation, but specifically plays a role in cells within the central nervous system [49]. A truncated version of KSR2 (T-KSR2) was found in mouse testes, which may play a role in male fertility [51]. …”

Section: Structural Analysis Of Ksr Proteinsmentioning

confidence: 99%

KSR as a therapeutic target for Ras-dependent cancers

Neilsen

Frodyma

Lewis

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction Targeting downstream effectors required for oncogenic Ras signaling is a potential alternative or complement to the development of more direct approaches targeting Ras in the treatment of Ras-dependent cancers. Areas covered Here we review literature pertaining to the molecular scaffold Kinase Suppressor of Ras (KSR) and its role in promoting signals critical to tumor maintenance. We summarize the phenotypes in knockout models, describe the role of KSR in cancer, and outline the structure and function of the KSR1 and KSR2 proteins. We then focus on the most recent literature that describes the crystal structure of the kinase domain of KSR2 in complex with MEK1, KSR-RAF dimerization particularly in response to RAF inhibition, and novel attempts to target KSR proteins directly. Expert opinion KSR is a downstream effector of Ras-mediated tumorigenesis that is dispensable for normal growth and development, making it a desirable target for the development of novel therapeutics with a high therapeutic index. Recent advances have revealed that KSR can be functionally inhibited using a small molecule that stabilizes KSR in an inactive conformation. The efficacy and potential for this novel approach to be used clinically in the treatment of Ras-driven cancers is still being investigated.

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Identification of a truncated kinase suppressor of Ras 2 mRNA in sperm

Abstract: HighlightsA truncated kinase suppressor of Ras 2 (T-KSR2) mRNA was identified.T-KSR2 is expressed exclusively in mouse testes and sperm.Analysis of T-KSR2 may enhance understanding of spermatogenesis and fertility.

Cited by 7 publications

References 28 publications

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2^−
/− mice

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2^−
/− mice

Ultrastructural study of spermatogenesis in KSR2 deficient mice

KSR as a therapeutic target for Ras-dependent cancers

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Identification of a truncated kinase suppressor of Ras 2 mRNA in sperm

Abstract: HighlightsA truncated kinase suppressor of Ras 2 (T-KSR2) mRNA was identified.T-KSR2 is expressed exclusively in mouse testes and sperm.Analysis of T-KSR2 may enhance understanding of spermatogenesis and fertility.

Cited by 7 publications

References 28 publications

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2 − /− mice

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2 − /− mice

Ultrastructural study of spermatogenesis in KSR2 deficient mice

KSR as a therapeutic target for Ras-dependent cancers

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Resources

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Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2^−
/− mice

Obesity-dependent dysregulation of glucose homeostasis in kinase suppressor of ras 2^−
/− mice