SPAK, a STE20/SPS1-related kinase that activates the p38 pathway

Johnston, A. D.; Naselli, Gaetano; Góñez, L. Jorge; Martin, RM; Harrison, Len C.; DeAizpurua, HJ

doi:10.1038/sj.onc.1203784

Cited by 133 publications

(153 citation statements)

References 35 publications

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“…SPAK, originally termed Ste20/SPS1-related proline-and alaninerich kinase 23 is under the control of AR in LNCaP. 24 Our own data confirm this observation.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S supporting

confidence: 67%

“…Expression of one kinase, SPAK, 23 increased in androgen-treated LNCaP, and SPAK expression was completely abrogated by the antiandrogen bicalutamide. 24 In addition, SPAK has been described as a kinase that activates the p38 MAP kinase pathway.…”

Section: Resultsmentioning

confidence: 97%

“…24 In addition, SPAK has been described as a kinase that activates the p38 MAP kinase pathway. 23 Moreover, p38 was identified as a kinase that phosphorylates several p53 Ser sites including Ser15. 2 This led us to examine SPAK expression in LNCaP treated with si-AR as well as in LNCaP cultured in SFC.…”

Section: Resultsmentioning

confidence: 99%

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MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

Rokhlin¹,

Scheinker²,

Taghiyev³

et al. 2008

Cancer Biology & Therapy

140

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We investigated whether knocking down AR expression effects apoptosis after treatment with different apoptosis-inducing agents. We found that siRNA AR (si-AR) significantly decreased apoptosis induced by topoisomerase inhibitors doxorubicin (DOX) and camptothecin (Campt). It is known that DNA double-strand break inducing agents leads to activation (phosphorylation) of p53 that in turn regulates the expression of a variety of apoptosis-related genes including microRNA(miR)-34a and 34b/c. We found that DOX induced five phosphorylation sites of p53 (Ser15, 20, 37, 46 and 392); all of these sites were inhibited by si-AR. Subsequently we identified three kinases, SPAK, MDC1 and CaMKII that are under AR control and two of them, MDC1 and CaMKII, apparently participate in p53 upstream events that resulted in p53 inhibition. Using qPCR we showed that the level of miR-34a increased by 3-fold after DOX, but no increase was found with si-AR. MiR-34c expression increased 27 fold after DOX and only by 2.7 times with si-AR. It appears that AR-dependent inhibition of p53 resulted in suppression of miR-34a and -34c expression. Importantly, DOX did not induce miR-34 in LNCaP grown in an androgen free medium or in AR-negative prostate cancer cell lines, DU145 and PC3. To directly investigate the role of miR-34 in DOX-mediated apoptosis, we transfected cells with anti-miR-34 oligonucleotides or with miR-34. We found that inhibition of individual miR-34, either 34a or 34c, or forced overexpression of miR-34a or miR-34c did not modulate DOX-mediated apoptosis. Only simultaneous inhibition or forced overexpression of both miR-34 resulted in modulation of DOX-mediated apoptosis. Taken together, our data indicate that cooperation between miR-34a and 34c plays an important role in AR-dependent p53-mediated apoptosis in prostate cancer.

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“…SPAK, originally termed Ste20/SPS1-related proline-and alaninerich kinase 23 is under the control of AR in LNCaP. 24 Our own data confirm this observation.…”

Section: © 2 0 0 8 L a N D E S B I O S C I E N C E D O N O T D I S supporting

confidence: 67%

Section: Resultsmentioning

confidence: 97%

See 1 more Smart Citation

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

Rokhlin¹,

Scheinker²,

Taghiyev³

et al. 2008

Cancer Biology & Therapy

140

View full text Add to dashboard Cite

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“…6 The kinase MST1 may act upstream of p38α and c-Jun N-terminal kinase (JNK) in response to oxidative stress. 27,28 In this study, we clearly demonstrated that c-Abl directly phosphorylates p38α and plays a critical role in the MPTP-induced pathogenesis of PD. However, the role of MST1 in c-Abl-mediated p38α activation requires further investigation.…”

Section: Discussionmentioning

confidence: 51%

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

Chen

et al. 2015

Cell Death Differ

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Oxidative stress is a major cause of sporadic Parkinson's disease (PD). Here, we demonstrated that c-Abl plays an important role in oxidative stress-induced neuronal cell death. C-Abl, a nonreceptor tyrosine kinase, was activated in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced acute PD model. Conditional knockout of c-Abl in neurons or treatment of mice with STI571, a c-Abl family kinase inhibitor, reduced the loss of dopaminergic neurons and ameliorated the locomotive defects induced by short-term MPTP treatment. By combining the SILAC (stable isotope labeling with amino acids in cell culture) technique with other biochemical methods, we identified p38α as a major substrate of c-Abl both in vitro and in vivo and c-Ablmediated phosphorylation is critical for the dimerization of p38α. Furthermore, p38α inhibition mitigated the MPTP-induced loss of dopaminergic neurons. Taken together, these data suggested that c-Abl-p38α signaling may represent a therapeutic target for PD. Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by bradykinesia, rigidity, tremor, and loss of dopaminergic neurons. 1 Familial mutations that cause PD have been identified, including in the genes that encode α-synuclein and leucine-rich repeat kinase 2 (LRRK2) that cause autosomal-dominant PD, and DJ-1, PINK1, and parkin that cause autosomal-recessive PD. 2 However, the majority of PD cases are sporadic. The cause of sporadic PD remains unknown, and the role of environmental toxins and genetic factors in sporadic PD is unclear. However, the evidence regarding postencephalitic PD and the discovery of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP)-induced Parkinsonism suggest that environmental toxins may be a major cause of sporadic PD. 3,4 The neurotoxins used to induce dopaminergic neurodegeneration, including 6-hydroxydopamine, MPTP, and rotenone, induce the formation of reactive oxygen species (ROS). ROS react with nucleic acids, proteins, and lipids to induce mitochondrial damage. Although oxidative stress plays a critical role in causing PD, the mechanisms underlying oxidative stress-induced PD remain unclear.The nonreceptor tyrosine kinase c-Abl is ubiquitously expressed and mediates a variety of extrinsic and intrinsic cell signaling activities, including growth factor signaling, cell adhesion, oxidative stress, and DNA damage. 5 Our group and other groups have reported that c-Abl plays an important role in oxidative stress-induced neuronal death. 6-8 Recently, Ko et al. 9 and Imam et al. 10 have reported that c-Abl phosphorylated Parkin and inhibited its E3 ligase activity that led to the neurotoxic accumulation of Parkin's substrates. α-Synuclein has also been reported to be substrates of c-Abl and to participate in PD pathogenesis. 9-11 The c-Abl inhibitor Nilotinib and INNO-406 have been reported prevents the loss of dopamine neurons and improves motor behavior in a murine PD model. [12][13][14] In this study, we demonstrated that c-Abl ...

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“…STRAD, a 48-kDa protein, is a pseudokinase that consists of a STE20-like kinase domain but lacks several residues that are indespensible for catalytic activity. STRAD resembles most closely the STE20 homologues SPAK (Johnston et al, 2000) and ILPIP (Sanna et al, 2002), or PAP kinase (Nishigaki et al, 2003). Whereas SPAK is a true kinase, it was later shown that ILPIP/PAPK is a pseudokinase, similarly to STRAD and that it also interacts with and activates LKB1.…”

Section: Introductionmentioning

confidence: 99%

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

Dorfman

Macara

2008

MBoC

109

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LKB1, a serine/threonine kinase, regulates cell polarity, metabolism, and cell growth. The activity and cellular distribution of LKB1 are determined by cofactors, STRAD␣ and MO25. STRAD␣ induces relocalization of LKB1 from the nucleus to the cytoplasm and stimulates its catalytic activity. MO25 stabilizes the STRAD␣/LKB1 interaction. We investigated the mechanism of nucleocytoplasmic transport of LKB1 in response to its cofactors. Although LKB1 is imported into the nucleus by importin-␣/␤, STRAD␣ and MO25 passively diffuse between the nucleus and the cytoplasm. STRAD␣ induces nucleocytoplasmic shuttling of LKB1. STRAD␣ facilitates nuclear export of LKB1 by serving as an adaptor between LKB1 and exportins CRM1 and exportin7. STRAD␣ inhibits import of LKB1 by competing with importin-␣ for binding to LKB1. MO25 stabilizes the LKB1-STRAD␣ complex but it does not facilitate its nucleocytoplasmic shuttling. Strikingly, the STRAD␤, isoform which differs from STRAD␣ in the N-and C-terminal domains that are responsible for interaction with export receptors, does not efficiently relocalize LKB1 from the nucleus to the cytoplasm. These results identify a multifactored mechanism to control LKB1 localization, and they suggest that the STRAD␤-LKB1 complex might possess unique functions in the nucleus. INTRODUCTIONPeutz-Jeghers cancer syndrome is caused by mutations in a gene encoding a serine/threonine kinase called LKB1 (Hemminki et al., 1998). This kinase is closely related to PAR-4, a protein required for polarization of the Caenorhabditis elegans zygote, and it has recently been implicated in the apical/basal polarization of mammalian epithelial cells (Baas et al., 2004). LKB1 is also involved in numerous cell signaling pathways that regulate cellular metabolism (Shaw et al., 2004Liang et al., 2007), cell growth, and responses to DNA damage (Wei et al., 2005;Setogawa et al., 2006;Zeng and Berger, 2006). LKB1 can phosphorylate and activate 13 protein kinases from the AMP-activated protein kinase family (Lizcano et al., 2004). However, the biological significance of this phosphorylation is still unclear for many of these kinases. The cellular localization and activity of LKB1 is controlled through its interaction with Ste20 Related Adaptor (STRAD) and an adapter protein, MO25 . STRAD, a 48-kDa protein, is a pseudokinase that consists of a STE20-like kinase domain but lacks several residues that are indespensible for catalytic activity. STRAD resembles most closely the STE20 homologues SPAK (Johnston et al., 2000) and ILPIP (Sanna et al., 2002), or PAP kinase (Nishigaki et al., 2003). Whereas SPAK is a true kinase, it was later shown that ILPIP/PAPK is a pseudokinase, similarly to STRAD and that it also interacts with and activates LKB1. Therefore, it was termed STRAD␤, whereas the original STRAD became known as STRAD␣ . The complex of LKB1 and STRAD␣ or -␤ is stabilized by MO25, a 40-kDa protein composed of ␣-helical repeats that are distantly related to the armadillo repeat domain (Milburn et al., 2004). MO25 binds STRAD ...

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SPAK, a STE20/SPS1-related kinase that activates the p38 pathway

Cited by 133 publications

References 35 publications

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

MicroRNA-34 mediates AR-dependent p53-induced apoptosis in prostate cancer

c-Abl–p38α signaling plays an important role in MPTP-induced neuronal death

STRADα Regulates LKB1 Localization by Blocking Access to Importin-α, and by Association with Crm1 and Exportin-7

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