KSR1 Is Required for Cell Cycle Reinitiation Following DNA Damage

Razidlo, Gina L.; Johnson, Holly L.; Stoeger, Scott M.; Cowan, Kenneth H.; Bessho, Tadayoshi; Lewis, Robert E.

doi:10.1074/jbc.m806457200

Cited by 12 publications

(14 citation statements)

References 71 publications

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“…Metastasis suppressor Nm23-H1 can bind directly to KSR1 and phosphorylate KSR1 at Ser 392 , and can therefore facilitate its degradation as a result of decreased ERK activation [35,36]. KSR1 was also required for cell-cycle reinitiation in response to DNA-damage agents such as mitomycin C [37]. Additionally, through modulation of PGC1α [PPARγ (peroxisome-proliferatoractivated receptor γ ) co-activator 1α] and ERRα (oestrogenrelated receptor α), KSR1 was demonstrated to induce oncogenic Ras-dependent anchorage-independent growth [38].…”

Section: The Roles Of Ksr1 In Various Biological Processes Ksr1 In Camentioning

confidence: 99%

The dual function of KSR1: a pseudokinase and beyond

Zhang

Koo

Stebbing

et al. 2013

Biochemical Society Transactions

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Protein kinases play a pivotal role in regulating many aspects of biological processes, including development, differentiation and cell death. Within the kinome, 48 kinases (~10%) are classified as pseudokinases owing to the fact that they lack at least one conserved catalytic residue in their kinase domain. However, emerging evidence suggest that some pseudokinases, even without the ability to phosphorylate substrates, are regulators of multiple cellular signalling pathways. Among these is KSR1 (kinase suppressor of Ras 1), which was initially identified as a novel kinase in the Ras/Raf pathway. Subsequent studies showed that KSR1 mainly functions as a platform to assemble different cellular components thereby facilitating signal transduction. In the present article, we discuss recent findings regarding KSR1, indicating that it has dual activity as an active kinase as well as a pseudokinase/scaffolding protein. Moreover, the biological functions of KSR1 in human disorders, notably in malignancies, are also reviewed.

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Section: The Roles Of Ksr1 In Various Biological Processes Ksr1 In Camentioning

confidence: 99%

The dual function of KSR1: a pseudokinase and beyond

Zhang

Koo

Stebbing

et al. 2013

Biochemical Society Transactions

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“…KSR1 is an essential scaffold protein of the Ras/Raf/MAPK cascade that facilitates the activation of ERK (3). Studies have shown that the expression of KSR1 is upregulated in many types of cancer and is required for cell proliferation, apoptosis and cell-cycle reinitiation (4)(5)(6). Moreover, KSR1 was confirmed to contribute to tumorigenesis through the MAPK cascade in a mouse model (7,8).…”

Section: Introductionmentioning

confidence: 99%

Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells

Liu

Qin

et al. 2015

Oncology Reports

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Kinase suppressor of Ras 1 (KSR1) is a scaffold protein that modulates the activation of the oncogenic mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling pathway. Ginkgo biloba extract (EGb) 761 has been demonstrated to possess antitumor activity that may be related to the KSR1-mediated ERK signaling pathway. However, the roles and its underlying mechanism in gastric cancer are unclear. In the present study, 62 gastric cancer and matched normal tissues were exploited for immunohistochemistry and real-time fluorescent quantitative PCR detection. Results of the immunohistochemistry showed that the expression of ERK1/2 and p-ERK1/2 was correlated to the expression of KSR1 and p-KSR1 in the gastric cancer tissues, and the overexpression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 was significantly associated with histological grade, TNM stage, lymph node and distant metastasis. Compared with the normal tissues, the relative mRNA copy values of KSR1, ERK1 and ERK2 in the cancer tissues were 2.43 ± 0.49, 2.10 ± 0.44 and 3.65 ± 0.94. In addition, the expression of KSR1, p-KSR1, ERK1/2 and p-ERK1/2 in human gastric cancer multidrug resistant SGC-7901/CDDP cells was higher than that in the SGC-7901 cells as detected by the methods of immunocytochemistry and western blot analysis. EGb 761 not only suppressed expression of these proteins induced by cisplatin (CDDP) and etoposide in SGC-7901 cells, but also inhibited expression of these proteins in the SGC-7901/CDDP cells. Meanwhile, the proliferation-suppressing and apoptosis-inducing capacities of CDDP and etoposide were enhanced following combined treatment with EGb 761. Moreover, EGb 761 reduced the malondialdehyde (MDA) content and elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in the tumor cells. These results confirmed that activation of the KSR1-mediated ERK1/2 signaling pathway may contribute to tumorigenesis, metastasis and chemoresistance of human gastric cancer. EGb 761 enhanced the chemotherapy sensitivity and reversed the chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells, and the underlying mechanism may be related to its antioxidative activity.

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“…Different scaffold proteins for the MAPK pathway regulate intracellular signaling by providing spatial and temporal specificity 30. One example is kinase suppressor of Ras, which binds Raf, Mek and Erk at the plasma membrane and has been described as a regulator of cell cycle reinitiation following DNA damage 31, cellular proliferation and transformation 32. We have shown that the localization of another MAPK scaffold complex with Mek partner 1 (MP1 or MAPBP) and its adaptor p14 (MAPBPIP) to late endosomes is required for the regulation of late endosomal traffic and proliferation 33, 34.…”

Section: Discussionmentioning

confidence: 99%

QIKS – Quantitative identification of kinase substrates

et al. 2010

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Signaling networks regulate cellular responses to external stimuli through post-translational modifications such as protein phosphorylation. Phosphoproteomics facilitate the large-scale identification of kinase substrates. Yet, the characterization of critical connections within these networks and the identification of respective kinases remain the major analytical challenge. To address this problem, we present a novel approach for the identification of direct kinase substrates using chemical genetics in combination with quantitative phosphoproteomics. Quantitative identification of kinase substrates (QIKS) is a novel-screening platform developed for the proteome-wide substrate-analysis of specific kinases. Here, we aimed to identify substrates of mitogen-activated protein kinase/Erk kinase (Mek1), an essential kinase in the mitogen-activated protein kinase cascade. An ATP analog-sensitive mutant of Mek1 (Mek1-as) was incubated with a cell extract from Mek1 deficient cells. Phosphorylated proteins were analyzed by LC-MS/MS of IMAC-enriched phosphopeptides, labeled differentially for relative quantification. The identification of extracellular regulated kinase 1/2 as the sole cytoplasmic substrates of MEK1 validates the applicability of this approach and suggests that QIKS could be used to identify substrates of a wide variety of kinases.

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KSR1 Is Required for Cell Cycle Reinitiation Following DNA Damage

Cited by 12 publications

References 71 publications

The dual function of KSR1: a pseudokinase and beyond

The dual function of KSR1: a pseudokinase and beyond

Ginkgo biloba extract enhances chemotherapy sensitivity and reverses chemoresistance through suppression of the KSR1-mediated ERK1/2 pathway in gastric cancer cells

QIKS – Quantitative identification of kinase substrates

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