Structural Biochemistry/sequestosome-1

Introduction
p62 is an atypical protein kinase C (PKC)-interacting protein that plays important roles in cellular functions. It interacts with several key components of various signaling mechanisms. p62 is required for tumour transformation, which makes it crucial for the control of cell growth and cancer. P62 or sequestosome-1 has been identified as a partner of the atypical protein kinase Cs (aPKCs) in unbiased screens. Initial studies showed that p62 controls localization of the aPKCs to the nuclear factor (NF)-κB cascade. Further studies show that in contrast to the relatively simple structure of Par-6, p62 is rich in protein interacting sequences, which demonstrates its role as a signaling hub. Cell proliferation under tumorigenic conditions requires that cells increase in size before division can take place. The survival of these cells depends on their ability fo active autophagy, reprogramme its metabolism, and control the production of toxic compounds, such as reactive oxygen species ROS and misfolded proteins. Cell divisions must be monitored and carried out in perfect sequences to avoid dramatic consequences, such as activation of tumorigenesis through genomic instability. These regulatory mechanisms could be rich sources of potential therapeutic targets in cancer. For example, the interference with the nutrient-sensing pathways could prevent cells from dividing. Studies were done previously to investigate the phenotype of p62-deficient mice to demonstrate the physiological role of p62 to control oesteoclastogenesis and bone remodeling.

P62 in the control of cell growth and autophagy
Recent studies using unbiased proteomic approach discovered the role for p62 in activation of mammalian target of rapamycin (mTOR) pathway. The mTOR pathway regulates “cell growth and autophagy that integrates nutrient sensing and cell-size control,” and is activated in many types of cancer. p62 specifically associates with mTORC1 – a multi-protein complex controlled by mTOR that channels a variety of signals into a coordinated protein synthesis and inhibiting autophagy. Recent studies discovered that “in p62-deficient cells, amino acid-mediated phosphorylation of the mTORC1 targets P70-S6 kinase (S6K) and eIF4E-binding protei 1 (4EBP1) is severely impareied and, in keeping with decreased mTORC1 activity autophage is upregulated.” p62 is also a substrate of autophagy, which makes a feedforward loop, which increases the activity of mTORC1. In conditions of oxygen deficiency and nutrient deprivation, the p62-mTORC1-autophagy loop could provide a safety mechanism to make sure that the cell death due to nutrients deprivation is irreversible. Studies show that the “Rag GTPase control amino acid-dependent mTORC1 activity by regulating mTORC1 translocation to a lysosomal associated membrane protein 2 (LAMP2)-positive compartment. p62 binds raptor and the Rags, which triggers the activation of the pathway favouring the formation of the active Rag dimer, through probably a p62 oligomerization mechanism. Constant findings support the need of p62 for the translocation of mTORC1 to the lysosomal surface as p62 was observed to be located at Rab7-psotitive late-endosomal membranes. This is also supported by mTORC1’s role in regulating endocytosis as a response to changes in environmental factors.

p62 and control of the oxidative stress response in cancer
The role of p62 in cell survival and tumorigenesis can be traced to the interation of p62 with tumour necrosis factor receptor associated facter (TRAF) 6 – inflammation signaling molecule, and the degradation of p62 by autophagy. Studies show strong correlation between autophagic pathways, inflammation-mediated cell toxicity and p62. For example, in live physiology, the genetic inactivation of key autophagy molecules increases p62 accumulation and hepatotoxicity that lead to liver tumours. p62 overexpression leads to chronic inflammation and cancer in the liver. Thus, p62 plays a crucial role in autophagy as a tumour suppressor, possibly through the suppression of ROS. There also seems to be a correlation between p62 overexpression to NRF2 activation through the ability of p62 to bond with Keap1, a negative regulator of NRF2 activation. In particular, there seems to be a linear correlation between the reduced autophagy and its subsequent accumulation of p62, which then activates NRF2 to decrease oxidative stress. However, other experimental data weakens the linear correlation between autophagy, p62, and oncogenesis, because while Ras-induced transformation required p62, it also increases autophagy. Perhaps p62 in fact behaves as a central hub that controls several survival mechanisms in Ras-transformed cells. “Ongenic Ras modulated p62 levels at a gene transcriptional level through a mechanism involving targeting of an activator protein (AP)-1 enhancer element in the p62 promoter. The removal of p62 prevents oncogenic transformation in an in vivo, “physiologically relevant, endogenous Ras-induced lung cancer model.” The wildtype mice developed in vitro the same cells expressing wild-type p62, which suggests that p62 phosphorylation by cdk1 serves to restrict cell transformation. Cdk1-mediated p62 phosphorylation restricts cell transformation by the control of mitotic exit. “When tumour cells express either wile type or non-phosphorylatable p62 exit mitosis and transition from mitosis to G1 faster than wild-type cells. An enhaced proportion of nonphosphorylatable p62-expressing cells displays lagging chromosomes and micronuclei, which are indicative of increased genome instability.” These observations demonstrate that p62 stimulates tumorigensis by controlling ROS levels that promotes cell survival, and also promotes premature exit from mitosis that increases proliferation rate and genome instability.

Conclusion
p62 plays a major role in cell transformation machinery, which affects processes such as cell growth, survival and mitosis. The role of p62 under non-pathological conditions is to control bone and metabolic homeostasis, which could suggest that p62 is indirectly in control of cancer, which makes it a potential therapeutic target in metastasis. p62 also plays a role in “maintaining metabolic homeostasis by restraining adipogenesis and promoting energy expenditure.” It is also demonstrated that obesity-induced inflammation and insulin resistance can promote at least some type of cancer, so the inactivation of p62 at an organismal level could promote the cancer progression if it results in enhanced adiposity and obesity.

Reference
Moscat, Jorge. and Diaz-Meco, Maria T. "p62: a versatile multitasker takes on cancer" Trends Biochem Sci. 2012 June; 37(6). Review.