Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Farag, Ahmed Karam; Roh, Eun Joo

doi:10.1002/med.21518

Cited by 76 publications

(89 citation statements)

References 216 publications

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“…Due to the current lack of a suitable antibody for detection of endogenous PEAK3, our analysis was conducted using a 3xFLAG-tagged human PEAK3 transiently expressed in HEK293T cells. Identified proteins that coimmunoprecipitated with PEAK3-3xFLAG can be categorized into several subgroups: (i) CrkII and CrkL, highly homologous adaptor proteins that regulate cell proliferation, adhesion, and cytoskeletal integrity downstream from receptor tyrosine kinases and integrins (29,30); (ii) 14-3-3 scaffold proteins (β, γ, η, and τ), which play diverse roles in signaling, including regulation of cell motility, survival, and intracellular protein trafficking (31); (iii) guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins for Rho family of small GTPases, including ASAP1 that participates in actin cytoskeletal dynamics and cell movement (32,33); and (iv) several proteins connected to the regulation of cell death and survival, including SIAH1 ubiquitin ligase (34), DRAK1 (35), and another 14-3-3 scaffold protein, 14-3-3σ, also known as SFN (36) (SI Appendix, Table S1). Collectively, this analysis suggests that PEAK3 plays a role in a number of functions involved in cell proliferation, survival, and motility.…”

Section: Peak3 Is a Distinct Member Of The Nkf3 Family Of Atypical Prmentioning

confidence: 99%

PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization

Lopez

Kung

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Members of the New Kinase Family 3 (NKF3), PEAK1/SgK269 and Pragmin/SgK223 pseudokinases, have emerged as important regulators of cell motility and cancer progression. Here, we demonstrate that C19orf35 (PEAK3), a newly identified member of the NKF3 family, is a kinase-like protein evolutionarily conserved across mammals and birds and a regulator of cell motility. In contrast to its family members, which promote cell elongation when overexpressed in cells, PEAK3 overexpression does not have an elongating effect on cell shape but instead is associated with loss of actin filaments. Through an unbiased search for PEAK3 binding partners, we identified several regulators of cell motility, including the adaptor protein CrkII. We show that by binding to CrkII, PEAK3 prevents the formation of CrkII-dependent membrane ruffling. This function of PEAK3 is reliant upon its dimerization, which is mediated through a split helical dimerization domain conserved among all NKF3 family members. Disruption of the conserved DFG motif in the PEAK3 pseudokinase domain also interferes with its ability to dimerize and subsequently bind CrkII, suggesting that the conformation of the pseudokinase domain might play an important role in PEAK3 signaling. Hence, our data identify PEAK3 as an NKF3 family member with a unique role in cell motility driven by dimerization of its pseudokinase domain.

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Section: Peak3 Is a Distinct Member Of The Nkf3 Family Of Atypical Prmentioning

confidence: 99%

PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization

Lopez

Kung

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Death-associated protein kinase 1 (DAPK, DAPk, DAPK1) is a multi-domain serine/threonine kinase regulated by calcium [27][28][29] . It was first identified for its role in mediating IFN-γ-induced cell death 30 , but subsequent evidence demonstrated involvement in apoptotic cell death induced by Fas 31 , TGF-β 32 , ceramide 33 , matrix detachment 34 , unliganded Netrin-1 receptor uncoordinated protein 5 homolog 2 (UNC5H2) 35 , or ER stress 36 .…”

Section: Introductionmentioning

confidence: 99%

Tumor suppressor death-associated protein kinase 1 inhibits necroptosis by p38 MAPK activation

Chou

Young

et al. 2020

Cell Death Dis

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Death-associated protein kinase 1 (DAPK1, DAPk, DAPK) is known for its involvement in apoptosis and autophagyassociated cell death. Here, we identified an unexpected function of DAPK1 in suppressing necroptosis. DAPK1deficiency renders macrophages and dendritic cells susceptible to necroptotic death. We also observed an inhibitory role for DAPK1 in necroptosis in HT-29 cells, since knockdown or knockout of DAPK1 in such cells increased their sensitivity to necroptosis. Increased necroptosis was associated with enhanced formation of the RIPK1-RIPK3-MLKL complex in these DAPK1-deficient cells. We further found that DAPK1-deficiency led to decreased MAPK activated kinase 2 (MK2) activation and reduced RIPK1 S321 phosphorylation, with this latter representing a critical step controlling necrosome formation. Most TNF signaling pathways, including ERK, JNK, and AKT, were not regulated by DAPK. In contrast, DAPK bound p38 MAPK and selectively promoted p38 MAPK activation, resulting in enhanced MK2 phosphorylation. Our results reveal a novel role for DAPK1 in inhibiting necroptosis and illustrate an unexpected selectivity for DAPK1 in promoting p38 MAPK-MK2 activation. Importantly, our study suggests that modulation of necroptosis and p38/MK2-mediated inflammation may be achieved by targeting DAPK1.

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“…Although DAPK1 has long been recognized as an important therapeutic target protein, only a few DAPK1 inhibitors have been reported and there is no clinical candidate to date (Farag & Roh, 2019). Apart from staurosporine, a broadspectrum kinase inhibitor (Omura et al, 1995), the first identified DAPK1 inhibitor was an aminopyridazine compound that was described in 2003 (Velentza et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Structural and thermodynamic analyses of interactions between death-associated protein kinase 1 and anthraquinones

Yokoyama

Wijaya

Kosaka

et al. 2020

Acta Cryst Sect D Struct Biol

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Death-associated protein kinase 1 (DAPK1) is a serine/threonine protein kinase that regulates apoptosis and autophagy. DAPK1 is considered to be a therapeutic target for amyloid-deposition, endometrial adenocarcinomas and acute ischemic stroke. Here, the potent inhibitory activity of the natural anthraquinone purpurin against DAPK1 phosphorylation is shown. Thermodynamic analysis revealed that while the binding affinity of purpurin is similar to that of CPR005231, which is a DAPK1 inhibitor with an imidazopyridazine moiety, the binding of purpurin was more enthalpically favorable. In addition, the inhibition potencies were correlated with the enthalpic changes but not with the binding affinities. Crystallographic analysis of the DAPK1-purpurin complex revealed that the formation of a hydrogen-bond network is likely to contribute to the favorable enthalpic changes and that stabilization of the glycine-rich loop may cause less favorable entropic changes. The present findings indicate that purpurin may be a good lead compound for the discovery of inhibitors of DAPK1, and the observation of enthalpic changes could provide important clues for drug development.

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Death‐associated protein kinase (DAPK) family modulators: Current and future therapeutic outcomes

Cited by 76 publications

References 216 publications

PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization

PEAK3/C19orf35 pseudokinase, a new NFK3 kinase family member, inhibits CrkII through dimerization

Tumor suppressor death-associated protein kinase 1 inhibits necroptosis by p38 MAPK activation

Structural and thermodynamic analyses of interactions between death-associated protein kinase 1 and anthraquinones

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