GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer

Hsu, Chung-Ping; Chuang, Huai‐Chia; Lee, Ming-Ching; Tsou, Hsiao‐Hui; Lee, Li-Wen; Li, Ju‐Pi; Tan, Tse‐Hua

doi:10.18632/oncotarget.9410

Cited by 26 publications

(30 citation statements)

References 29 publications

(31 reference statements)

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“…GLK is a highly desirable drug target for disease areas that include Still's disease (in which patients present with clinical symptoms similar to systemic lupus erythrmatosus), breast cancer, and possibly nonsmall cell lung cancer . We have observed that GLK, like Map4k4, has a glycine right before the Tyrosine in the activation loop and forms an activation loop‐swapped dimer [Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that GLK effects apoptosis by modulating BH3‐only proteins at the post‐transcriptional level, resulting in activation of the mitochondrial‐dependent intrinsic apoptosis pathway . Recently GLK upregulation has been found to be associated with recurrence of nonsmall cell lung cancer …”

Section: Introductionmentioning

confidence: 99%

“…7 Recently GLK upregulation has been found to be associated with recurrence of nonsmall cell lung cancer. 8 The GCK-I family includes GCK (Map4k2), GLK (Map4k3), HGK (Map4k4), KHS or GCKR (Map4k5), and HPK1 (Map4k1). The GCK-I family of kinases have a similar architecture-the kinase domain located at its N-terminus followed by modular domains that enable protein-protein interactions-namely the central proline-rich domain (including PEST sequences that could mediate degradation) and the C-terminal SH3 binding regions and Citron-homology domains.…”

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confidence: 99%

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Germinal‐center kinase‐like kinase co‐crystal structure reveals a swapped activation loop and C‐terminal extension

et al. 2016

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Germinal-center kinase-like kinase (GLK, Map4k3), a GCK-I family kinase, plays multiple roles in regulating apoptosis, amino acid sensing, and immune signaling. We describe here the crystal structure of an activation loop mutant of GLK kinase domain bound to an inhibitor. The structure reveals a weakly associated, activation-loop swapped dimer with more than 20 amino acids of ordered density at the carboxy-terminus. This C-terminal PEST region binds intermolecularly to the hydrophobic groove of the N-terminal domain of a neighboring molecule. Although the GLK activation loop mutant crystallized demonstrates reduced kinase activity, its structure demonstrates all the hallmarks of an "active" kinase, including the salt bridge between the C-helix glutamate and the catalytic lysine. Our compound displacement data suggests that the effect of the Ser170Ala mutation in reducing kinase activity is likely due to its effect in reducing substrate peptide binding affinity rather than reducing ATP binding or ATP turnover. This report details the first structure of GLK; comparison of its activation loop sequence and P-loop structure to that of Map4k4 suggests ideas for designing inhibitors that can distinguish between these family members to achieve selective pharmacological inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Germinal‐center kinase‐like kinase co‐crystal structure reveals a swapped activation loop and C‐terminal extension

et al. 2016

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“…GLK is activated by stimuli including ultraviolet radiation and several proinflammatory cytokines [84], and has clear roles in the pathogenesis of both autoimmune disease and cancer [85]. Clinically, GLK overexpression predicts poor overall and progression-free survival in non-small-cell lung carcinoma (NSCLC) [86], though the mechanisms through which GLK contributes to disease pathogenesis are not clear at this time. However, emerging evidence suggests that GLK regulates T-cell activation via IL-17A signaling [87].…”

Section: Other Mapk Family Membersmentioning

confidence: 99%

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

et al. 2020

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Mitogen-activated protein kinase (MAPK) signaling networks serve to regulate a wide range of physiologic and cancer-associated cell processes. For instance, a variety of oncogenic mutations often lead to hyperactivation of MAPK signaling, thereby enhancing tumor cell proliferation and disease progression. As such, several components of the MAPK signaling network have been proposed as viable targets for cancer therapy. However, the contributions of MAPK signaling extend well beyond the tumor cells, and several MAPK effectors have been identified as key mediators of the tumor microenvironment (TME), particularly with respect to the local immune infiltrate. In fact, a blockade of various MAPK signals has been suggested to fundamentally alter the interaction between tumor cells and T lymphocytes and have been suggested a potential adjuvant to immune checkpoint inhibition in the clinic. Therefore, in this review article, we discuss the various mechanisms through which MAPK family members contribute to T-cell biology, as well as circumstances in which MAPK inhibition may potentiate or limit cancer immunotherapy.

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“…Approximately 85% of lung cancers are nonsmall cell lung cancers (NSCLC) [2,3] , and although the number of surgical candidates has increased [1] , only 15-30% of the patients are suitable for surgical resection with a curative intent [2,4] .…”

Section: Introductionmentioning

confidence: 99%

Recurrence and Risk Factors for Relapse in Patients with Non-Small Cell Lung Cancer Treated by Surgery with Curative Intent

et al. 2017

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Introduction: Surgery remains the potentially curative treatment for early-stage non-small cell lung cancer (NSCLC). Despite this, tumor recurrence is the most common cause of treatment failure after surgery. Methods: Data were collected retrospectively from clinical files of patients who underwent lung surgery for NSCLC from January 2008 to December 2012 in a University Hospital. Demographic data, tumor characteristics, type of surgery and recurrence were recorded. A comparison of the distribution of variables using adjustment tests was made. Results: The study included 102 patients, 68.6% were male with a mean age of 63.7 ± 9.3 years old. The majority of tumors had a peripheral location (72.5%) and consisted of adenocarcinomas (61.8%). The most frequently performed surgery was lobectomy. Recurrence was noted in 43.1% of cases. Mean disease-free survival was 57.9 ± 3.8 months. Multifactorial analyses showed that stage IIIA, tumor located in other lobes than the right lower lobe and pleural invasion were independent predictors of recurrence. Conclusion: Our recurrence rate was similar to those in the international literature. As in other studies, we found a positive relation between the lymphatic permeation and pleural invasion and the risk of lung cancer recurrence. We consider that some characteristics of the tumor should be assessed to define alternative modalities of treatment and follow-up in order to predict and rapidly recognize the recurrence.

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GLK/MAP4K3 overexpression associates with recurrence risk for non-small cell lung cancer

Cited by 26 publications

References 29 publications

Germinal‐center kinase‐like kinase co‐crystal structure reveals a swapped activation loop and C‐terminal extension

Germinal‐center kinase‐like kinase co‐crystal structure reveals a swapped activation loop and C‐terminal extension

Mitogen-Activated Protein Kinase Inhibitors and T-Cell-Dependent Immunotherapy in Cancer

Recurrence and Risk Factors for Relapse in Patients with Non-Small Cell Lung Cancer Treated by Surgery with Curative Intent

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