Scaffold proteins of MAP-kinase modules

Dhanasekaran, Danny N.; Kashef, Kimia; Lee, Clement; Xu, Hua; Reddy, E. Premkumar

doi:10.1038/sj.onc.1210411

Cited by 251 publications

(224 citation statements)

References 165 publications

(354 reference statements)

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“…35,36 In this study, however, elevated JNK was found in Jsap1:Jlp dKO neurons and mice ( Figure 7). As described below, ablating the scaffold proteins JSAP1 and JLP itself would not directly cause the activation of JNK.…”

Section: Discussioncontrasting

confidence: 49%

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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Section: Discussioncontrasting

confidence: 49%

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

et al. 2015

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“…16 The JNK signaling interaction is well known to play an important regulatory role in cell proliferation, differentiation, apoptosis, cellular transformation, and tumor cell growth, and may be equally important for the outcome of SPAG9 expression in the cervix. 16,27,28 To our knowledge, the mechanism underlying the association between SPAG9 and carcinogenesis is still unclear. Perhaps the overexpression of SPAG9 changes the stability or kinetics of MAPK signaling pathways, leading to facilitation of cell invasion and migration; this warrants further studies.…”

Section: Discussionmentioning

confidence: 99%

Sperm‐associated antigen 9 is a biomarker for early cervical carcinoma

Garg

Kanojia

Salhan

et al. 2009

Cancer

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“…At the same time, they exclude other related components that operate in parallel cascades, insulating a MAPK module from undesired interferences. [77] In addition, scaffolds play important roles in the spatial selectivity of ERK signals: KSR1 acts preferentially upon ERK signals emanating from PM cholesterol-rich domains; [78] MP-1 regulates ERK in endosomes; [79] Sef at the GC; [80] and Paxillin at focal adhesions. [81] b-Arrestins are abundant in clathrin-coated pits.…”

Section: Some Space For Erksmentioning

confidence: 99%

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

2010

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Recent discoveries have suggested the concept that intracellular signals are the sum of multiple, site-specified subsignals, rather than single, homogeneous entities. In the context of cancer, searching for compounds that selectively block subsignals essential for tumor progression, but not those regulating ''house-keeping'' functions, could help in producing drugs with reduced side effects compared to compounds that block signaling completely. The Ras-ERK pathway has become a paradigm of how space can differentially shape signaling. Today, we know that Ras proteins are found in different plasma membrane microdomains and endomembranes. At these localizations, Ras is subject to site-specific regulatory mechanisms, distinctively engaging effector pathways and switching-on diverse genetic programs to generate different biological responses. The Ras effector pathway leading to ERKs activation is also under strict, space-related regulatory processes. These findings may open a gate for aiming at the Ras-ERK pathway in a spatially restricted fashion, in our quest for new anti-tumor therapies.

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Scaffold proteins of MAP-kinase modules

Cited by 251 publications

References 165 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

Sperm‐associated antigen 9 is a biomarker for early cervical carcinoma

The Ras‐ERK pathway: Understanding site‐specific signaling provides hope of new anti‐tumor therapies

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