Specialized proteins with long cytoplasmic tails

Health

Proteins of aging and their localization in the cell

By Juman Hijab

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Original date: July 9, 2023  

Updated: August 17, 2023

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Specialized proteins with long cytoplasmic tails

Berkshire Community College Bioscience Image Library. Epithelial Tissues: Brush Border in Simple Columnar Epithelium. Flickr.com, April 26, 2018.

Proteins of aging

In this article, I am going to list 5 proteins that are associated with cell senescence. Abnormal expression or activation of those proteins can transform them into proteins of aging. 


Interestingly, those 5 proteins preferentially localize on the basolateral membrane of polarized cells.


This is one of several articles on the particular characteristics that define proteins that can be abnormally linked to aging cells. 

Basolateral membranes

Our human body has 20,000 genes that produce different types of proteins (each protein is further modified giving rise to multiple variations for any given protein (1). As the protein is produced in the rough endoplasmic reticulum, it is then packaged in rounded structures (vesicles) that make their way to the Golgi apparatus. From there proteins are distributed to different cellular subdivisions. 


Basolateral segregation of proteins

Cells show specialization by having a top and a bottom orientation. Thus, neurons have a cell body and an axon; intestinal cells have a basolateral membrane and an apical membrane that faces the lumen; gland cells also have a basolateral membrane and an apical membrane that faces the inside of the gland.

In the image above, one can see elongated epithelial cells seemingly stuck together with the nucleus sitting very close to the basal membrane. If you click on the image, you can see the very fine "brush border" on the apical membrane.

The apical or "top" membrane of the cell is typically very different from the  basolateral or "bottom" membrane. Each section has its own function within the cell and displays a different set of membrane proteins. Thus, specialization happens as the cell segregates different types of proteins to different parts of the cell.

Five proteins that localize to the basolateral membrane

Dysfunctional expression or activation of certain proteins can lead to cell senescence. These "proteins of aging" tend to segregate to the basolateral membranes of the cell.


Here are 5 proteins that preferentially localize to the basolateral membranes of the cell. 

  • Epidermal Growth Factor Receptor (EGFR) (234)
  • Transforming Growth Factor beta receptor (56, 78)
  • Monocyte chemoattractant protein-1(MCP-1) (91011)
  • Interleukin 6 Receptor (121314)
  • Receptor for Advanced Glycation Endproducts (RAGE) (1516)

What is fascinating is that some of those proteins (for example, EGFR) are important in healthy cellular growth and proliferation. However, the cell is propelled down a senescent path when those proteins are dysfunctionally activated. 

Basolateral proteins and senescence; proteins of aging

Basolateral proteins and senescence; proteins of aging

Pro-inflammatory factors induce senescence in nearby healthy cells

Unfortunately, senescent cells often exhibit a senescence-associated secretory phenotype (SASP), characterized by the secretion of various pro-inflammatory factors. And those same factors promote senescence in nearby healthy cells.

It's not good. This is why many therapies look at blocking those membrane proteins, as demonstrated in the table above. 


As you can imagine, there are two sides to the coin. EGFR proteins are related to cancer cell growth. Thus, blocking EGFR proteins (for example, with Herceptin) also induces cancer cell senescence (17).

Related articles in this series

  1. Proteins of aging and their localization in the cell (this article): Dysfunctional or hyper-functional membrane proteins that induce aging often reside in the basolateral regions of the cellular membrane.
  2. Why it is important to learn about Senescence-associated secretory phenotype (SASP) proteins: Senescent cells accumulate over time and contribute to age-related diseases. They do this primarily by secreting Senescence-associated Secretory Phenotype (SASP) proteins. 
  3. Senescent cells display unhealthy acidification of the cytoplasm: There are multiple pathways all cascading to generate increased in cytoplasmic acid. These create a positive feedback loop that sets the cell up for a vicious cycle of dysfunctional intracellular organelles and ongoing  intracellular acidosis.
  4. An unusual attribute of senescence-inducing factors: Pro-inflammatory factors tend to have more acidic isoelectric point, with more acidic side groups. The evidence suggests that there is a correlation between acidic side-groups, isoelectric point, and senescence-inducing factors. 

References

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  2. Wieduwilt MJ, Moasser MM. The epidermal growth factor receptor family: biology driving targeted therapeutics. Cell Mol Life Sci. 2008 May;65(10):1566-84. doi: 10.1007/s00018-008-7440-8. PMID: 18259690; PMCID: PMC3060045.
  3. Cotton CU, Hobert ME, Ryan S, Carlin CR. Basolateral EGF receptor sorting regulated by functionally distinct mechanisms in renal epithelial cells. Traffic. 2013 Mar;14(3):337-54. doi: 10.1111/tra.12032. Epub 2012 Dec 28. PMID: 23205726; PMCID: PMC4304763.
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  5. Yin X, Kang JH, Andrianifahanana M, Wang Y, Jung MY, Hernandez DM, Leof EB. Basolateral delivery of the type I transforming growth factor beta receptor is mediated by a dominant-acting cytoplasmic motif. Mol Biol Cell. 2017 Oct 1;28(20):2701-2711. doi: 10.1091/mbc.E17-05-0334. Epub 2017 Aug 2. PMID: 28768825; PMCID: PMC5620377.
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  9. Dzenko KA, Andjelkovic AV, Kuziel WA, Pachter JS. The chemokine receptor CCR2 mediates the binding and internalization of monocyte chemoattractant protein-1 along brain microvessels. J Neurosci. 2001 Dec 1;21(23):9214-23. doi: 10.1523/JNEUROSCI.21-23-09214.2001. PMID: 11717355; PMCID: PMC6763923.
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  11. Zhang C, Yang M. Current Options and Future Directions for NAFLD and NASH Treatment. Int J Mol Sci. 2021 Jul 15;22(14):7571. doi: 10.3390/ijms22147571. PMID: 34299189; PMCID: PMC8306701.
  12. Martens AS, Bode JG, Heinrich PC, Graeve L. The cytoplasmic domain of the interleukin-6 receptor gp80 mediates its basolateral sorting in polarized madin-darby canine kidney cells. J Cell Sci. 2000 Oct;113 ( Pt 20):3593-602. doi: 10.1242/jcs.113.20.3593. PMID: 11017875.
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  16. Liu J, Huang K, Cai GY, Chen XM, Yang JR, Lin LR, Yang J, Huo BG, Zhan J, He YN. Receptor for advanced glycation end-products promotes premature senescence of proximal tubular epithelial cells via activation of endoplasmic reticulum stress-dependent p21 signaling. Cell Signal. 2014 Jan;26(1):110-21. doi: 10.1016/j.cellsig.2013.10.002. Epub 2013 Oct 7. PMID: 24113348.
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Tags

aging, senescence


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