What is the Difference Between TSC1 and TSC2

The main difference between TSC1 and TSC2 is that TSC1 or hamartin is a protein expressed in some of the adult tissues, and mainly involves in cell adhesion whereas TSC2 or tuberin is a protein responsible for regulating cell growth, proliferation and differentiation. Furthermore, the reported frequency of mutations in the TSC1 gene is less, around 10%, while the reported frequency of mutations in the TSC2 gene is comparatively high, around 30%.  

TSC1 and TSC2 are two types of proteins produced by the two tumor suppressor genes TSC1 and TSC2, respectively. The de novo mutations of these genes are often associated with the Tuberous sclerosis complex (TSC), an autosomal dominant disease. 

Key Areas Covered 

1. What is TSC1
     – Definition, Molecular Genetics, Importance
2. What is TSC2
     – Definition, Molecular Genetics, Importance
3. What are the Similarities Between TSC1 and TSC2
     – Outline of Common Features
4. What is the Difference Between TSC1 and TSC2
     – Comparison of Key Differences

Key Terms 

mTOR Pathway, Mutations, TSC1, TSC2, Tuberous Sclerosis Complex (TSC), Tumor Suppressor Genes

What is TSC1 

TSC1 or hamartin is a protein expressed based on the information on the tumor suppressor gene TSC1. The expression of this gene occurs in several tissues of humans and the gene product is a hydrophilic protein with 1164 amino acids, playing a key role in the regulation of cell adhesion. Furthermore, the protein hamartin does not show homology with any protein found in vertebrates.  

Figure 1: The mTOR Pathway

Moreover, the TSC1 protein binds with the TSC2 protein through their respective coiled-coil domains, forming an intracellular protein complex. This complex is responsible for integrating signals, which regulate the activation of Rheb (a Ras homolog enriched in brain) in the activation pathway of mTOR (mammalian target of rapamycin) kinase. The regulation of the activation of the mTOR pathway, in turn, regulates the translation of a significant portion of cellular proteins. These proteins include those responsible for the control of cell growth and proliferation. 

What is TSC2 

TSC2 or tuberin is a protein expressed based on the information on another tumor suppressor gene known as the TSC2. The expression of the gene produces a 5.5 kb transcript and a protein with 1807 amino acids. Especially, a 163 amino acid long, conserved portion near the C-terminal region exhibits homology with some of the proteins in the GTPases proteins in the Ras superfamily. Thus, tuberin is a GTPase activating protein that regulates the GTP binding and the hydrolysis of the proteins in the Ras superfamily, in turn regulating the cell growth, proliferation, and differentiation. 

Figure 2: Clusters of Facial Angiofibromas in Tuberous Sclerosis

However, TSC2 involves in the formation of the TSC2: TSC1 complex, in the mTOR pathway. Therefore, the loss of function mutations in either TSC2 or TSC1 proteins lead to the abnormal production of end products of the pathway, promoting tumorigenesis. Tuberous sclerosis, aka tuberous sclerosis complex (TSC) is a disease condition formed due to a mutation of one of the two tumor suppressor genes TSC1 or TSC2. This disease is characterized by the formation of multiple tumors in different organs and skin manifestations. It is an autosomal dominant neurocutaneous and progressive disorder. 

Similarities Between TSC1 and TSC2 

• TSC1 and TSC2 are two gene products of tumor suppressor genes in the human genome. 
• They perform distinct regulatory functions. 
• Also, the TSC1 and TSC2 proteins form a complex which has a function in the mTOR pathway, regulating cell growth, translation factor activation, and cell nutrition.  
• Furthermore, the de novo mutations of the corresponding genes result in Tuberous sclerosis complex (TSC), an autosomal dominant disease. 
• Besides, the loss of function mutations in these two genes result in tumorigenesis. 

Difference Between TSC1 and TSC2 

Definition 

TSC1 refers to a protein produced by humans and encoded by the TSC1 gene while TSC2 refers to a protein produced by humans and encoded by the TSC2 gene. 

Other Names 

While TSC1 protein is also known as hamartin, TSC2 protein is also known as tuberin. 

Function 

The respective function of each protein is the main difference between TSC1 and TSC2. While TSC1 protein regulates cell adhesion, TSC2 protein regulates the Ras family proteins and helps to regulate cell growth, proliferation, and differentiation. 

Location of the Gene 

Furthermore, the location of the gene is another difference between TSC1 and TSC2. The location of the TSC1 gene is 9q34.13 in the human genome while the location of the TSC2 gene in the human gene is 16p13.3. 

Size of the Gene 

Size of the gene is also a major difference between TSC1 and TSC2. The size of the TSC1 gene is 53 kb while the size of the TSC2 gene is 43 kb. 

Number of Exons in the Gene 

Also, one other difference between TSC1 and TSC2 is that TSC1 gene contains 23 exons while TSC2 gene contains 41 exons.  

Size of the Protein 

TSC1 protein contains 1164 amino acids, 130 kDa in size while TSC2 protein contains 1807 amino acids,198 kDa in size. Hence, this is also a difference between TSC1 and TSC2.

Protein Homology 

Moreover, TSC1 protein does not show homology with any other vertebrate protein while TSC2 protein contains a conserved 163 amino acid region, which has homology with the GTPase proteins of the Ras superfamily. Thus, this is an important difference between TSC1 and TSC2.

Conclusion 

TSC1 or hamartin is a protein encoded by the TSC1 gene on chromosome 9. It is responsible for the regulation of cell adhesion. In comparison, TSC2 or tuberin is a protein encoded by the TSC2 gene on chromosome 16. It has a regulatory function in cell growth, proliferation, and differentiation. Moreover, the two proteins interact with each other to form a complex, which plays a key role in cell growth and cell division. However, the main difference between TSC1 and TSC2 is their individual regulatory function. 

References:

1. Rosset, Clévia et al. “TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review” Genetics and molecular biology vol. 40,1 (2017): 69-79. Available Here.

Image Courtesy:

1. “MTOR-pathway-v1.7” By Charles betz (CC BY 3.0) via Commons Wikimedia 
2. “TuberousSclerosis-Rayer” By Pierre François Olive Rayer (1793 – 1867) – Paolo Curatolo (Editor) (2003). Tuberous Sclerosis Complex : From Basic Science to Clinical Phenotypes. MacKeith Press. ISBN 1-898-68339-5. Page 138. Chapter 9: Dermatological and Stomatological Manifestations. Sergiusz Jóźwiak and Robert Schartz. (Public Domain) via Commons Wikimedia