Tuberous Sclerosis Complex 2 (TSC2), also known as Tuberin, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that in humans is encoded by the ''TSC2''

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

Function

Mutations in this gene lead to

tuberous sclerosis Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination ...

. Its gene product is believed to be a

tumor suppressor A tumor suppressor gene (TSG), or anti-oncogene, is a gene that regulates a cell during cell division and replication. If the cell grows uncontrollably, it will result in cancer. When a tumor suppressor gene is mutated, it results in a loss or red ...

and is able to stimulate specific

GTPase GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...

s. Hamartin coded by the gene

TSC1 Tuberous sclerosis 1 (TSC1), also known as hamartin, is a protein that in humans is encoded by the ''TSC1'' gene. Function TSC1 functions as a co-chaperone which inhibits the ATPase activity of the chaperone Hsp90 (heat shock protein-90) and de ...

functions as a facilitator of Hsp90 in chaperoning of Tuberin, therefore preventing its ubiquitination and degradation in the proteasome.

Alternative splicing Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...

results in multiple transcript variants encoding different

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

s of the protein. Mutations in TSC2 can cause

Lymphangioleiomyomatosis Lymphangioleiomyomatosis (LAM) is a rare, progressive and systemic disease that typically results in cystic lung destruction. It predominantly affects women, especially during childbearing years. The term sporadic LAM is used for patients with LAM ...

, a disease caused by the enlargement of tissue in the lungs, creating cysts and tumours and causing difficulty breathing. Because Tuberin regulates cell size, along with the protein Hamartin, mutations to

and TSC2 genes may prevent the control of cell growth in the lungs of individuals.

Cell Pathology

Cells from individuals with pathogenic mutations in the TSC2 gene display depletion of

lysosome A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

s, impairment of

autophagy Autophagy (or autophagocytosis; from the Ancient Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent re ...

, and abnormal accumulation of

glycogen Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. The polysaccharide structure represents the main storage form of glucose in the body. Glycogen functions as one o ...

. Defects in the autophagy-lysosome pathway are associated with excessive

ubiquitination Ubiquitin is a small (8.6 kDa) regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ''ubiquitously''. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Fo ...

and degradation of LC3 and LAMP1/2 proteins.

Signaling Pathways

Pharmacological inhibition of ERK1/2 restores

GSK3β Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...

activity and protein synthesis levels in a model of tuberous sclerosis. The defective degradation of glycogen by the autophagy-lysosome pathway is, at least in part, independent of impaired regulation of

mTORC1 mTORC1, also known as mammalian target of rapamycin complex 1 or mechanistic target of rapamycin complex 1, is a protein complex that functions as a nutrient/energy/redox sensor and controls protein synthesis. mTOR Complex 1 (mTORC1) is compo ...

and is restored by the combined use of PKB/Akt and mTORC1 pharmacological inhibitors.

Interactions

TSC2 functions within a multi-protein complex knowns as the TSC complex which consists of the core proteins TSC2, TSC1, and TBC1D7. TSC2 has been reported to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with several other proteins that are not a part of the TSC complex including: *

AKT1 RAC(Rho family)-alpha serine/threonine-protein kinase is an enzyme that in humans is encoded by the ''AKT1'' gene. This enzyme belongs to the AKT subfamily of serine/threonine kinases that contain SH2 (Src homology 2-like) protein domains. It i ...

, *

AXIN1 Axin-1 is a protein that in humans is encoded by the ''AXIN1'' gene. Function This gene encodes a cytoplasmic protein which contains a regulation of G-protein signaling (RGS) domain and a dishevelled and axin (DIX) domain. The encoded prote ...

, *

FOXO1 Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the ''FOXO1'' gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glyco ...

, *

GSK3B Glycogen synthase kinase-3 beta, (GSK-3 beta), is an enzyme that in humans is encoded by the ''GSK3B'' gene. In mice, the enzyme is encoded by the Gsk3b gene. Abnormal regulation and expression of GSK-3 beta is associated with an increased suscept ...

, *

Hsp70 The 70 kilodalton heat shock proteins (Hsp70s or DnaK) are a family of conserved ubiquitously expressed heat shock proteins. Proteins with similar structure exist in virtually all living organisms. Intracellularly localized Hsp70s are an importa ...

Hsp90 Hsp90 (heat shock protein 90) is a chaperone protein that assists other proteins to fold properly, stabilizes proteins against heat stress, and aids in protein degradation. It also stabilizes a number of proteins required for tumor growth, ...

MAPK1 Mitogen-activated protein kinase 1, (MAPK 1), also known as ERK2, is an enzyme that in humans is encoded by the ''MAPK1'' gene. Function The protein encoded by this gene is a member of the MAP kinase family. MAP kinases, also known as extracel ...

, *

PTK2 PTK2 protein tyrosine kinase 2 (PTK2), also known as focal adhesion kinase (FAK), is a protein that, in humans, is encoded by the ''PTK2'' gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion (how cells stick to ...

, * PAM, *

PRKAA1 5'-AMP-activated protein kinase catalytic subunit alpha-1 is an enzyme that in humans is encoded by the ''PRKAA1'' gene. The protein encoded by this gene belongs to the serine/threonine protein kinase family. It is the catalytic subunit of the 5' ...

, *

RAP1A Ras-related protein Rap-1A is a protein that in humans is encoded by the ''RAP1A'' gene. Function The product of this gene belongs to the family of Ras-related proteins. These proteins share approximately 50% amino acid identity with the clas ...

, * RHEB, *

RPS6KA1 Ribosomal protein S6 kinase alpha-1 is an enzyme that in humans is encoded by the ''RPS6KA1'' gene. Function This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 nonidentical k ...

, *

UBE3A Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the ''UBE3A'' gene. This enzyme is involved in targeting proteins for degradation within cells. Protein degradation ...

and *

YWHAZ 14-3-3 protein zeta/delta (14-3-3ζ) is a protein that in humans is encoded by the ''YWHAZ'' gene on chromosome 8. The protein encoded by this gene is a member of the 14-3-3 protein family and a central hub protein for many signal transduction pat ...

References

External links

GeneReviews/NIH/NCBI/UW entry on Tuberous Sclerosis Complex or Bourneville Disease
{{GTP-binding protein regulators