SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway

Li, Yingqiu; Hu, Junru; Vita, Randi; Sun, Binggang; Tabata, Hiroki; Altman, Amnon

doi:10.1038/sj.emboj.7600125

Cited by 85 publications

(84 citation statements)

References 41 publications

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“…The expression of endogenous SPAK was inhibited by infection with recombinant lentivirus constructs pLSL-puro expressing siRNA hairpin under control of the RNA H1 promoter. 3 The structures of two SPAK gene-specific oligonucleotides complementary to human SPAK mRNA 21 were as follows: 5'-CCCAGGCAAGAACGTGTA-3' and 5'-ATTCAAGC-CATGAGTCAGT-3' corresponding to nucleotides 255-273 and 334-352 respectively. LNCaP was infected with lentiviruses either with one si-SPAK or with mixture of two (labeled DB).…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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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“…During T-cell activation, SPAK is involved in TCR/CD28-induced AP-1 activation through interactions with the PKCh molecule via its C-terminal region. 108 Receptor expressed in lymphoid tissues and its homologs RELL1 and RELL2 are non-canonical members of TNFR family that may be distinct from those of classical members in terms of signaling. The C-terminal domain of SPAK/OSR1 may bind to the 'RFRV' motif found in the cytoplasmic domain of receptor expressed in lymphoid tissue subfamily members, leading to phosphorylation of receptor expressed in lymphoid tissue and downstream signaling.…”

Section: Gck-vi Kinases Contribute To Regulation Of T-cell Activationmentioning

confidence: 99%

Germinal center kinases in immune regulation

Yin

Shi

et al. 2012

Cell Mol Immunol

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“…4,7 OSR1 and SPAK have been suggested to be coupled to cellular events such as cell differentiation, cytoskeleton rearrangement, cell proliferation, and transformation. 3,[11][12][13][14][15] In addition, extensive biochemical and physiological studies demonstrate that OSR1 and SPAK are also involved in the regulation of ion homeostasis and volume control in mammalian cells. For example, during hyperosmotic stress, OSR1 and SPAK interact with and activate NKCC1 (Na…”

Section: Introductionmentioning

confidence: 99%

Crystal structure of domain‐swapped STE20 OSR1 kinase domain

2009

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OSR1 (oxidative stress-responsive-1) and SPAK (Ste20/Sps1-related proline/alanine-rich kinase) belong to the GCK-VI subfamily of Ste20 group kinases. OSR1 and SPAK are key regulators of NKCCs (Na2 cotransporters) and activated by WNK family members (with-no-lysine kinase), mutations of which are known to cause Gordon syndrome, an autosomal dominant form of inherited hypertension. The crystal structure of OSR1 kinase domain has been solved at 2.25 Å . OSR1 forms a domain-swapped dimer in an inactive conformation, in which P11 loop and aEF helix are swapped between dimer-related monomers. Structural alignment with nonswapped Ste20 TAO2 kinase indicates that the integrity of chemical interactions in the kinase domain is well preserved in the domain-swapped interfaces. The OSR1 kinase domain has now been added to a growing list of domain-swapped protein kinases recently reported, suggesting that the domainswapping event provides an additional layer of complexity in regulating protein kinase activity.

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SPAK kinase is a substrate and target of PKCθ in T-cell receptor-induced AP-1 activation pathway

Cited by 85 publications

References 41 publications

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

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

Germinal center kinases in immune regulation

Crystal structure of domain‐swapped STE20 OSR1 kinase domain

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