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Cytoskeletal Activity

The cytoskeleton, composed of actin filaments, intermediate filaments and microtubules, regulates cell motility, shape and division, all vital to proper cell structure and function. A variety of genes control cytoskeletal activity and influence processes like muscle contraction, vesicular transport and chromosomal segregation, highlighting its importance to human health.

Exploring cytoskeletal signaling: Key questions and insights

Learn more about the intricate world of cytoskeletal dynamics and signaling pathways and their roles in cell movement, polarity and health

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What role does the ARP-WASP complex play in actin nucleation?

The actin-related protein 2/actin-related protein 3 (Arp2/3) complex is activated by WASP (Wiskott–Aldrich syndrome protein) family proteins (8). Upon activation, the ARP2/3 complex nucleates branched actin filaments on the sides of preexisting actin filaments, the first step in actin polymerization, which generates the protrusive forces required in cell movement (9, 4).

What is the significance of Cdc42 signaling in cell polarity?

Cdc42 is a member of the Rho GTPase family of intracellular molecular switches regulating multiple signaling pathways involved in actomyosin organization, cell-to-cell adhesion, cell cycle regulation, cell proliferation and actin-based morphogenesis. It also plays a critical role in regulating cell polarity. The formation and maintenance of cell polarity are essential for cellular processes, including differentiation, chemotaxis, morphogenesis, cell movement and cell division (10).

The Cdc42 acts as a molecular switch that is open in the GTP-bound state and closed in the GDP-bound state. This cycling between an inactive GDP-bound state and an active GTP-bound state is regulated by intracellular molecules guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs). GEFs initiate the exchange of GDP for GTP to activate Cdc42, while GAP promotes its GTPase activity, leading to the transition of Cdc42 to its inactive state, and GDIs inhibit reactivation (11).

When active, Cdc42 recruits and regulates various downstream effectors proteins that regulate the actin cytoskeleton and cell polarity, including N-WASP and p21-activated protein kinases (PAK) (12).

What is the function of PAK signaling in cytoskeletal dynamics?

PAKs (p21-activated kinases) are a family of serine/threonine protein kinases consisting of PAK1–6. They are effectors of GTPases Rac and Cdc42 that are essential to cytoskeletal dynamics, cell survival and proliferation.

PAK activation by Rac and Cdc42 leads to the phosphorylation of substrates that regulate cytoskeletal dynamics, including LIM kinase, p41-ARC, filamin A, Op18/stathmin and TCoB.

The LIM kinase is the most researched substrate of Rac and Cdc42 (13). It phosphorylates the actin-regulatory protein cofilin to inhibit its ability to depolymerize actin filaments, thus promoting filament accumulation and stability by preventing depolymerization (14).

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What are calpain proteases, and how do they regulate cellular mechanics and cytoskeletal functions?

Calpains are a 15-member class of calcium-dependent intracellular cysteine proteases. They are localized to the cytosol and mitochondria. Calpain activation and catalytic activity are tightly regulated by cytosolic calcium (Ca2+) and its endogenous inhibitor, calpastatin (22, 23).

Calpain regulates many cellular functions, such as cell signaling, cytoskeletal remodeling, cell differentiation, apoptosis and necrosis by targeting cytoskeletal and plasma membrane-associated proteins like α-fodrin, neurofilaments, ion channels and growth factor receptors (24).

Dysregulation of calpain activation and activity has been implicated in many diseases involving the brain, eyes, heart, vascular system, lungs, pancreas, kidneys and skeletal muscle,  highlighting its critical role in maintaining cellular function and integrity (23).

What are the health implications of dysregulated cytoskeletal signaling pathways?

The actin cytoskeleton is essential for many cellular functions. Hence, any abnormalities in its regulation or functioning can cause or contribute to diseases, including cancer, neurological disorders, cardiovascular diseases and Wiskott-Aldrich syndrome (6).

References and further reading

  1. National Cancer Institute https://www.cancer.gov/publications/dictionaries/cancer-terms/def/cytoskeleton (Accessed June 27, 2024)
  2. Fletcher DA, Mullins RD. Cell mechanics and the cytoskeleton. Nature. 2010;463(7280):485-492.
  3. National Institutes of Health https://www.nih.gov/news-events/nih-research-matters/new-mechanism-cell-movement-revealed (Accessed June 27, 2024)
  4. Svitkina T. The Actin Cytoskeleton and Actin-Based Motility. Cold Spring Harb Perspect Biol. 2018;10(1):a018267. Published 2018 Jan 2.
  5. ScienceDirect https://www.sciencedirect.com/topics/neuroscience/myosin-ii#:~:text=Myosin%20II%20is%20a%20well,filaments%20within%20the%20growth%20cone  (Accessed June 27, 2024)
  6. Lee SH, Dominguez R. Regulation of actin cytoskeleton dynamics in cells. Mol Cells. 2010;29(4):311-325.
  7. Yamazaki D, Kurisu S, Takenawa T. Regulation of cancer cell motility through actin reorganization. Cancer Sci. 2005;96(7):379-386.
  8. Rodnick-Smith M, Luan Q, Liu SL, Nolen BJ. Role and structural mechanism of WASP-triggered conformational changes in branched actin filament nucleation by Arp2/3 complex. Proc Natl Acad Sci U S A. 2016;113(27):E3834-E3843.
  9. Chavali SS, Chou SZ, Cao W, Pollard TD, De La Cruz EM, Sindelar CV. Cryo-EM structures reveal how phosphate release from Arp3 weakens actin filament branches formed by Arp2/3 complex [published correction appears in Nat Commun. 2024 Mar 15;15(1):2354. doi: 10.1038/s41467-024-46804-9]. Nat Commun. 2024;15(1):2059. Published 2024 Mar 6.
  10. Melendez J, Grogg M, Zheng Y. Signaling role of Cdc42 in regulating mammalian physiology. J Biol Chem. 2011;286(4):2375-2381.
  11. Xiao XH, Lv LC, Duan J, et al. Regulating Cdc42 and Its Signaling Pathways in Cancer: Small Molecules and MicroRNA as New Treatment Candidates. Molecules. 2018;23(4):787. Published 2018 Mar 29.
  12. Hirsch DS, Pirone DM, Burbelo PD. A new family of Cdc42 effector proteins, CEPs, function in fibroblast and epithelial cell shape changes. J Biol Chem. 2001;276(2):875-883.
  13.  Ye DZ, Field J. PAK signaling in cancer. Cell Logist. 2012;2(2):105-116.
  14. Best M, Gale ME, Wells CM. PAK-dependent regulation of actin dynamics in breast cancer cells. Int J Biochem Cell Biol. 2022;146:106207.
  15. Gresset A, Sondek J, Harden TK. The phospholipase C isozymes and their regulation. Subcell Biochem. 2012;58:61-94.
  16. ScienceDirect https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/phospholipase-c (Accessed June 27, 2024)
  17. Cristofanilli M, Akopian A. Calcium channel and glutamate receptor activities regulate actin organization in salamander retinal neurons. J Physiol. 2006;575(Pt 2):543-554.
  18. Yang Q, Zhang XF, Van Goor D, et al. Protein kinase C activation decreases peripheral actin network density and increases central nonmuscle myosin II contractility in neuronal growth cones. Mol Biol Cell.
  19. Mosaddeghzadeh N, Ahmadian MR. The RHO Family GTPases: Mechanisms of Regulation and Signaling. Cells. 2021;10(7):1831. Published 2021 Jul 20.
  20. Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 2006;16(10):522-529.
  21. Croisé P, Estay-Ahumada C, Gasman S, Ory S. Rho GTPases, phosphoinositides, and actin: a tripartite framework for efficient vesicular trafficking. Small GTPases. 2014;5:e29469.
  22. Griggs RB, Yermakov LM, Susuki K. Formation and disruption of functional domains in myelinated CNS axons. Neurosci Res. 2017 Mar;116:77-87. 
  23. Potz BA, Abid MR, Sellke FW. Role of Calpain in Pathogenesis of Human Disease Processes. J Nat Sci. 2016;2(9):e218.
  24. Momeni HR. Role of calpain in apoptosis. Cell J. 2011;13(2):65-72.

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