JSAP1, a Novel Jun N-Terminal Protein Kinase (JNK)-Binding Protein That Functions as a Scaffold Factor in the JNK Signaling Pathway

Ito, Michihiko; Yoshioka, Katsuji; Akechi, Mizuho; Yamashita, Shinya; Takamatsu, Nobuhiko; Sugiyama, Kenji; Hibi, Masahiko; Nakabeppu, Yusaku; Shiba, Tadayoshi; Yamamoto, Ken

doi:10.1128/mcb.19.11.7539

Cited by 264 publications

(310 citation statements)

References 55 publications

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“…Substitutions and deletions in cDNAs were introduced by overlapping PCR, as described previously. 7 All PCR products were verified by sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…3 Neuronal kinesin-1 often transports its cargoes through adaptor proteins such as c-Jun NH 2 -terminal kinase (JNK)-interacting protein 1 (JIP1) and JNK/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JIP3 or Sunday Driver). 4 The JIP protein family includes JIP1, 5 JIP2, 6 JSAP1/JIP3 (Ito et al 1999; Kelkar et al 2000) and JNK-associated leucine zipper protein (JLP). 9 Splice variants of JLP are known as JIP4 (Kelkar et al 2005) or SPAG9.…”

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confidence: 99%

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JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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Axonal transport is critical for neuronal development and function, and defective axonal transport has been implicated in neurodegenerative diseases. However, how axonal transport is regulated, or how defective transport leads to neuronal degeneration, remains unclear. Here, we report that c-Jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) and JNK-associated leucine zipper protein (JLP) are essential for postnatal brain development. Mice with a double-knockout (dKO) in Jsap1 and Jlp in the dorsal telencephalon developed progressive neuron loss. Using a primary neuron culture system with induced disruption of targeted genes, combined with gene rescue experiments, we show that JSAP1 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy. We also show that the binding of JSAP1 and JLP to kinesin-1 heavy chain is crucial for interactions between kinesin-1 and microtubules. Furthermore, we describe a molecular mechanism by which defective kinesin-1-dependent axonal transport in Jsap1:Jlp dKO neurons causes axonal degeneration and subsequent neuronal death. JNK hyperactivation because of increased intra-axonal Ca 2+ in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca 2+ -dependent protease calpain. Our results indicate that axonal JNK may relocate to the nucleus in a dynein-dependent manner, where it activates the transcription factor c-Jun, resulting in neuronal death. Taken together, our data establish JSAP1 and JLP as positive regulators of kinesin-1-dependent axonal transport, which prevents neuronal degeneration.

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“…Substitutions and deletions in cDNAs were introduced by overlapping PCR, as described previously. 7 All PCR products were verified by sequencing.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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“…NM_009007 and NM_010303, respectively) were obtained by PCR and subcloned into BamHI/SalI-digested pBabeblast. To introduce nucleotide substitutions into cDNAs encoding G a13 and the small GTPase Rac1, to create constitutively active forms of G a13 (G a13 Q226L) and Rac1 (Rac1G12V), site-directed mutagenesis was carried out by overlapping PCR as described previously (7). The region of the cytomegalovirus promoter in the plasmid vector pcDNA3 (Invitrogen, Carlsbad, CA, USA) was amplified by PCR and inserted into pWZL-blast to generate pWZL-CMV-blast.…”

Section: Methodsmentioning

confidence: 99%

“…JLP is broadly expressed, and is structurally related to JNK/stress-activated protein kinase-associated protein 1 (JSAP1 or JNK-interacting protein 3), a scaffold protein for JNK cascades (7)(8)(9).…”

mentioning

confidence: 99%

The Scaffold Protein c-Jun NH2-Terminal Kinase-associated Leucine Zipper Protein Regulates Cell Migration through Interaction with the G Protein G 13

Davaakhuu

Tuvshintugs

Endo

et al. 2008

Journal of Biochemistry

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Scaffold proteins for MAP kinase (MAPK) signalling modules play an important role in the specific and efficient signal transduction of the relevant MAPK cascades. Here, we investigated the function of the scaffolding protein c-Jun NH 2 -terminal kinase (JNK)-associated leucine zipper protein (JLP) by depleting it in cultured cells using a short hairpin RNA (shRNA) against human JLP. HeLa and DLD-1 cells stably expressing the shRNA showed a defect in cell migration. The re-expression of fulllength shRNA-resistant mouse JLP rescued the impaired cell migration of the JLPdepleted HeLa cells; whereas, a C-terminal deletion mutant of mouse JLP, which failed to bind the G protein G a13 , showed little or no effect on the cell migration defect. Furthermore, although a constitutively active G a13 enhanced the migration of control HeLa cells, the G a13 -induced cell migration was significantly suppressed in the JLP-depleted HeLa cells. Taken together, these results suggest that JLP regulates cell migration through an interaction with G a13 .Key words: cell migration, MAP kinase, p38, RNA interference, scaffold protein.Abbreviations: DMEM, Dulbecco's modified Eagle's medium; EDTA, ethylenediaminetetraacetic acid; GST, glutathione S-transferase; HEK, human embryonic kidney; JLP, JNK-associated leucine zipper protein; JNK, c-Jun NH2-terminal kinase; JSAP1, JNK/stress-activated protein kinase-associated protein 1; KD, knockdown; MAPK, MAP kinase; PCNA, proliferating cell nuclear antigen; PCR, polymerase chain reaction; shRNA, short hairpin RNA.MAP kinase (MAPK) cascades transmit signals through the sequential phosphorylation and activation of threetier kinase modules, consisting of MAPK kinase kinase, MAPK kinase and MAPK. Mammalian MAPK signalling pathways play a key role in multiple cellular functions, such as proliferation, migration and apoptosis (1, 2). The specificity of MAPK signalling is mediated, at least in part, by scaffold proteins. Scaffold proteins for MAPK cascades organize the MAPK signalling components into functional modules, thereby enabling the efficient activation of specific MAPK pathways (3-5). The scaffolding complexes also protect the signalling components within the relevant MAPK modules from undesired activation by other signalling molecules in cells.c-Jun NH 2 -terminal kinase (JNK)-associated leucine zipper protein (JLP) was originally identified as a binding protein for the transcription factor Max, and further biochemical study indicated that JLP functions as a scaffold protein for the JNK and p38 MAPK signalling modules (6). JLP is broadly expressed, and is structurally related to JNK/stress-activated protein kinase-associated protein 1 (JSAP1 or JNK-interacting protein 3), a scaffold protein for JNK cascades (7-9).Studies of JLP have mainly focused on identifying its interacting proteins, which include kinesin light chain 1 and G a13 , the a-subunit of the heteromeric G 13 protein (10,11). JLP has also been reported to play an important role in myogenesis by interacting with the cell-surface p...

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“…Recent studies show that SEK-1/MKK-4 is involved in JNK signaling during apoptosis progression (28). Accordingly, we examined whether SEK-1/MKK-4 participates in ionizing radiation -induced JNK activation and subsequent mitochondrial cell death.…”

Section: Sek-1/mkk-4 Involvement In Jnk Signaling During Radiation-inmentioning

confidence: 99%

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

Kim

Choi

Park

et al. 2008

Molecular Cancer Research

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Exposure of cells to ionizing radiation induces activation of multiple signaling pathways that play critical roles in determining cell fate. However, the molecular basis for cell death or survival signaling in response to radiation is unclear at present. Here, we show opposing roles of the c-jun NH 2 -terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways in the mitochondrial cell death in response to ionizing radiation in human cervical cancer cells. Ionizing radiation triggered Bax and Bak activation, Bcl-2 down-regulation, and subsequent mitochondrial cell death. Inhibition of JNK completely suppressed radiation-induced Bax and Bak activation and Bcl-2 down-regulation. Dominant-negative forms of stress-activated protein kinase/extracellular signal-regulated kinase kinase 1 (SEK-1)/mitogen-activated protein kinase kinase-4 (MKK-4) inhibited JNK activation. Radiation also induced phosphoinositide 3-kinase (PI3K) activation. Interestingly, inhibition of PI3K effectively attenuated radiation-induced mitochondrial cell death and increased clonogenic survival. Inhibition of PI3K also suppressed SEK-1/MKK-4 and JNK activation, Bax and Bak activation, and Bcl-2 down-regulation. In contrast, inhibition of p38 MAPK led to enhanced Bax and Bak activation and mitochondrial cell death. RacN17, a dominant-negative form of Rac1, inhibited p38 MAPK activation and increased Bax and Bak activation. Exposure of cells to radiation also induced selective activation of c-Src among Src family kinases. Inhibition of c-Src by pretreatment with Src family kinase inhibitor PP2 or small interfering RNA targeting of c-Src attenuated radiation-induced p38 MAPK and Rac1 activation and enhanced Bax and Bak activation and cell death. Our results support the notion that the PI3K-SEK-1/MKK-4-JNK pathway is required for the mitochondrial cell death in response to radiation, whereas the c-Src-Rac1-p38 MAPK pathway plays a cytoprotective role against mitochondrial cell death.

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JSAP1, a Novel Jun N-Terminal Protein Kinase (JNK)-Binding Protein That Functions as a Scaffold Factor in the JNK Signaling Pathway

Cited by 264 publications

References 55 publications

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

The Scaffold Protein c-Jun NH2-Terminal Kinase-associated Leucine Zipper Protein Regulates Cell Migration through Interaction with the G Protein G 13

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

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