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 residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

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

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

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 combinatio ...

. 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 (biology), 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 ...

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 ...

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 d ...

functions as a facilitator of

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

in chaperoning of tuberin, therefore preventing its ubiquitination and degradation in the

proteasome Proteasomes are essential protein complexes responsible for the degradation of proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases. Proteasomes are found inside all e ...

Alternative splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative RNA splicing, splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene ma ...

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 and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

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 LA ...

, 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 that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

s, impairment of

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

, 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. It is the main storage form of glucose in the human body. Glycogen functions as one of three regularly used forms ...

. 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 19 ...

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 susce ...

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 comp ...

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

Interactions

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

, *

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 protei ...

, *

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 susce ...

, *

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 and play crucial roles in the development of can ...

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 extracell ...

, *

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, * 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 ...

, *

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 cell (biology), cells. ...

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 p ...

References

External links

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