The Atypical Protein Kinase C-interacting Protein p62 Is a Scaffold for NF-κB Activation by Nerve Growth Factor

Wooten, Marie W.; Seibenhener, M. Lamar; Mamidipudi, Vidya; Diaz-Meco, Marı́a T.; Barker, Philip A.; Moscat, Jorge

doi:10.1074/jbc.c000869200

Cited by 159 publications

(181 citation statements)

References 24 publications

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“…Association of p62/SQSTM1 with TRAF6 is necessary for NFkB signaling from the interleukin 1 receptor (IL-1R) and the nerve growth factor receptor (NGF-R) (Sanz et al 2000;Wooten et al 2001). Upon stimulation of these receptors, p62/SQSTM1 binds to TRAF6 through the TB domain and to aPKC through the PB1, bringing the kinase into the complex for activation.…”

Section: Structurementioning

confidence: 99%

“…This complex forms upon stimulation of the TNF-R and is necessary to activate NFkB, since disrupting the ZZ domain or reducing the expression of p62/SQSTM1 impairs TNFα-mediated NFkB activation (Sanz et al 1999). In addition to TNF-R, the interleukin-1β receptor (IL-1βR) and the nerve growth factor receptors TrkA and p75 NTR recruit p62/SQSTM1 to facilitate signaling to NFkB (Sanz et al 2000;Wooten et al 2001). These receptors signal downstream by recruiting the ubiquitin-ligase TRAF6, which subsequently binds to p62/SQSTM1 on the TB domain and to interleukin-1 receptor-associated kinase (IRAK).…”

Section: Biological Functionsmentioning

confidence: 99%

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p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

120

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Advanced age is characterized by increased incidence of many chronic, noninfectious diseases that impair the quality of living of the elderly and pose a major burden on the healthcare systems of developed countries. These diseases are characterized by impaired or altered function at the tissue and cellular level, which is a hallmark of the aging process. Age-related impairments are likely due to loss of homeostasis at the cellular level, which leads to the accumulation of dysfunctional organelles and damaged macromolecules, such as proteins, lipids, and nucleic acids. Intriguingly, aging and age-related diseases can be delayed by modulating nutrient signaling pathways converging on the target of rapamycin (TOR) kinase, either by genetic or dietary intervention. TOR signaling influences aging through several potential mechanisms, such as autophagy, a degradation pathway that clears the dysfunctional organelles and damaged macromolecules that accumulate with aging. Autophagy substrates are targeted for degradation by associating with p62/SQSTM1, a multidomain protein that interacts with the autophagy machinery. p62/SQSTM1 is involved in several cellular processes, and its loss has been linked to accelerated aging and to age-related pathologies. In this review, we describe p62/SQSTM1, its role in autophagy and in signaling pathways, and its emerging role in aging and age-associated pathologies. Finally, we propose p62/ SQSTM1 as a novel target for aging studies and ageextending interventions.

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Section: Structurementioning

confidence: 99%

Section: Biological Functionsmentioning

confidence: 99%

p62/SQSTM1 at the interface of aging, autophagy, and disease

Bitto

Lerner

Nacarelli

et al. 2014

AGE

120

View full text Add to dashboard Cite

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“…In light of these findings, it has been suggested that p62 may serve as a platform for pathway interaction between NGF signals mediated by the trkA and p75 NTR . 39 Elucidating the diversity of functions mediated by NGF (and pro-NGF) signaling through different neurotrophin receptors is currently an active area of research (for reviews, see Guo et al 40 and Gabriel et al 41 ). Not surprisingly, there is evidence that NF-kB will not work alone, but may function in concert with other pathways to regulate complex neuronal processes such as plasticity, survival and dendrite development.…”

Section: Growth Factor Signalingmentioning

confidence: 99%

Roles for NF-κB in nerve cell survival, plasticity, and disease

2006

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Here we review evidence of roles for NF-jB in the regulation of developmental and synaptic plasticity, and cell survival in physiological and pathological settings. Signaling pathways modulating NF-jB activity include those engaged by neurotrophic factors, neurotransmitters, electrical activity, cytokines, and oxidative stress. Emerging findings support a pivotal role for NF-jB as a mediator of transcription-dependent enduring changes in the structure and function of neuronal circuits. Distinct subunits of NF-jB may uniquely affect cognition and behavior by regulating specific target genes. NF-jB activation can prevent the death of neurons by inducing the production of antiapoptotic proteins such as Bcl-2, IAPs and manganese superoxide dismutase (Mn-SOD). Recent findings indicate that NF-jB plays important roles in disorders such as epilepsy, stroke, Alzheimer's and Parkinson's diseases, as well as oncogenesis. Molecular pathways upstream and downstream of NF-jB in neurons are being elucidated and may provide novel targets for therapeutic intervention in various neurological disorders.

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“…1,2 Through its multi-domain structure, p62/SQSTM1 interacts specifically with key signaling proteins, including atypical PKC family members, NF-kB, and mTOR to control cellular responses. [3][4][5][6][7] p62/SQSTM1 functions also as a key mediator of autophagy. Through its interaction with LC3, an essential protein involved in autophagy, p62/SQSTM1 selectively directs ubiquitinated substrates to autophagosomes leading to their subsequent degradation in lysosomes.…”

mentioning

confidence: 99%

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

et al. 2014

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The p62/SQSTM1 adapter protein has an important role in the regulation of several key signaling pathways and helps transport ubiquitinated proteins to the autophagosomes and proteasome for degradation. Here, we investigate the regulation and roles of p62/SQSTM1 during acute myeloid leukemia (AML) cell maturation into granulocytes. Levels of p62/SQSTM1 mRNA and protein were both significantly increased during all-trans retinoic acid (ATRA)-induced differentiation of AML cells through a mechanism that depends on NF-jB activation. We show that this response constitutes a survival mechanism that prolongs the life span of mature AML cells and mitigates the effects of accumulation of aggregated proteins that occurs during granulocytic differentiation. Interestingly, ATRA-induced p62/SQSTM1 upregulation was impaired in maturation-resistant AML cells but was reactivated when differentiation was restored in these cells. Primary blast cells of AML patients and CD34 þ progenitors exhibited significantly lower p62/SQSTM1 mRNA levels than did mature granulocytes from healthy donors. Our results demonstrate that p62/SQSTM1 expression is upregulated in mature compared with immature myeloid cells and reveal a prosurvival function of the NF-jB/SQSTM1 signaling axis during granulocytic differentiation of AML cells. These findings may help our understanding of neutrophil/granulocyte development and will guide the development of novel therapeutic strategies for refractory and relapsed AML patients with previous exposure to ATRA.

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The Atypical Protein Kinase C-interacting Protein p62 Is a Scaffold for NF-κB Activation by Nerve Growth Factor

Cited by 159 publications

References 24 publications

p62/SQSTM1 at the interface of aging, autophagy, and disease

p62/SQSTM1 at the interface of aging, autophagy, and disease

Roles for NF-κB in nerve cell survival, plasticity, and disease

p62/SQSTM1 upregulation constitutes a survival mechanism that occurs during granulocytic differentiation of acute myeloid leukemia cells

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