familial thoracic aortic aneurysm and dissection At least nine TGFBR2 gene mutations have been identified in people with familial thoracic aortic aneurysm and dissection (familial TAAD). This disorder involves problems with the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. The aorta can weaken and stretch, causing a bulge in the blood vessel wall (an aneurysm). Stretching of the aorta may also lead to a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can cause life-threatening internal bleeding. The TGFBR2 gene mutations that cause familial TAAD disturb signal transduction. The disturbed signaling can impair cell growth and development. It is not known how these changes result in the specific aortic abnormalities associated with familial TAAD. Loeys-Dietz syndrome More than 80 mutations in the TGFBR2 gene have been found to cause Loeys-Dietz syndrome type II. Loeys-Dietz syndrome affects connective tissue, which gives structure and support to blood vessels, the skeleton, and other parts of the body. This type of Loeys-Dietz syndrome is characterized by blood vessel abnormalities and skeletal deformities. Most TGFBR2 gene mutations that cause Loeys-Dietz syndrome change single protein building blocks (amino acids) in TGF-β receptor type 2, resulting in a receptor with little or no function. Although the receptor has severely reduced function, cell signaling occurs at an even greater intensity than normal. Researchers speculate that the activity of proteins in this signaling pathway is increased to compensate for the reduction in TGF-β receptor type 2 activity; however the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway disrupts development of connective tissue and various body systems and leads to the varied signs and symptoms of Loeys-Dietz syndrome type II. Some TGFBR2 gene mutations that cause Loeys-Dietz syndrome type II have also been found to cause familial TAAD (described above). Affected families can include some individuals with Loeys-Dietz syndrome and others with familial TAAD. cancers Some TGFBR2 gene mutations are acquired during a person's lifetime and are present only in certain cells. These changes are called somatic mutations and are not inherited. People with somatic mutations in the TGFBR2 gene appear to have an increased risk of developing various cancers. Somatic TGFBR2 gene mutations probably disrupt the signaling process that helps regulate cell division. Unchecked cell division can lead to the formation of tumors, particularly when TGFBR2 gene mutations occur in the colon, rectum, and esophagus. It is estimated that 30 percent of cancerous (malignant) colon tumors have TGFBR2 gene mutations in their cells.

     The TGFBR2 gene provides instructions for making a protein called transforming growth factor-beta (TGF-β) receptor type 2. This receptor transmits signals from the cell surface into the cell through a process called signal transduction. Through this type of signaling, the environment outside the cell affects activities inside the cell such as stimulation of cell growth and division. To carry out its signaling function, the TGF-β receptor type 2 spans the cell membrane, so that one end of the protein projects from the outer surface of the cell (the extracellular domain) and the other end remains inside the cell (the intracellular domain). A protein called TGF-β attaches (binds) to the extracellular domain of the TGF-β receptor type 2, which turns on (activates) the receptor and allows it to bind to a similar receptor on the cell surface. These three proteins form a complex, which triggers signal transduction by activating other proteins in this signaling pathway. Signals triggered through the TGF-β receptor complex prompt various responses by the cell, including the growth and division (proliferation) of cells, the maturation of cells to carry out specific functions (differentiation), cell movement (motility), and controlled cell death (apoptosis). Because TGF-β receptor type 2 keeps cells from growing and dividing too rapidly or in an uncontrolled way, it is also important in suppressing the formation of tumors.

The following transcription factors affect gene expression:

• NF-kappaB
• AhR
• STAT3
• NF-kappaB1
• HNF-4alpha1
• HNF-4alpha2
• Sp1

Molecular Function:

• Transmembrane Receptor Protein Serine/Threonine Kinase Activity
• Signal Transducer, Downstream Of Receptor, With Serine/Threonine Kinase Activity
• Transforming Growth Factor Beta-Activated Receptor Activity
• Transforming Growth Factor Beta Receptor Activity, Type Ii
• Atp Binding
• Glycosaminoglycan Binding
• Type I Transforming Growth Factor Beta Receptor Binding
• Type Iii Transforming Growth Factor Beta Receptor Binding
• Smad Binding
• Metal Ion Binding
• Transforming Growth Factor Beta Binding

Biological Processes:

• Blood Vessel Development
• Branching Involved In Blood Vessel Morphogenesis
• Vasculogenesis
• Response To Hypoxia
• In Utero Embryonic Development
• Heart Looping
• Positive Regulation Of Mesenchymal Cell Proliferation
• Lens Development In Camera-Type Eye
• Positive Regulation Of Tolerance Induction To Self Antigen
• Positive Regulation Of B Cell Tolerance Induction
• Positive Regulation Of T Cell Tolerance Induction
• Outflow Tract Septum Morphogenesis
• Membranous Septum Morphogenesis
• Outflow Tract Morphogenesis
• Atrioventricular Valve Morphogenesis
• Tricuspid Valve Morphogenesis
• Cardiac Left Ventricle Morphogenesis
• Endocardial Cushion Fusion
• Growth Plate Cartilage Chondrocyte Growth
• Protein Phosphorylation
• Receptor-Mediated Endocytosis
• Apoptotic Process
• Transforming Growth Factor Beta Receptor Signaling Pathway
• Common-Partner Smad Protein Phosphorylation
• Notch Signaling Pathway
• Smoothened Signaling Pathway
• Gastrulation
• Brain Development
• Heart Development
• Embryo Implantation
• Aging
• Response To Nutrient
• Positive Regulation Of Cell Proliferation
• Response To Mechanical Stimulus
• Response To Glucose
• Regulation Of Gene Expression
• Positive Regulation Of Epithelial Cell Migration
• Positive Regulation Of Epithelial To Mesenchymal Transition
• Peptidyl-Serine Phosphorylation
• Peptidyl-Threonine Phosphorylation
• Negative Regulation Of Transforming Growth Factor Beta Receptor Signaling Pathway
• Animal Organ Regeneration
• Activation Of Protein Kinase Activity
• Embryonic Hemopoiesis
• Wound Healing
• Regulation Of Cell Proliferation
• Myeloid Dendritic Cell Differentiation
• Positive Regulation Of Skeletal Muscle Tissue Regeneration
• Response To Estrogen
• Positive Regulation Of Angiogenesis
• Response To Steroid Hormone
• Digestive Tract Development
• Positive Regulation Of Smooth Muscle Cell Proliferation
• Embryonic Cranial Skeleton Morphogenesis
• Positive Regulation Of Nk T Cell Differentiation
• Palate Development
• Negative Regulation Of Cardiac Muscle Cell Proliferation
• Pathway-Restricted Smad Protein Phosphorylation
• Ventricular Septum Morphogenesis
• Bronchus Morphogenesis
• Trachea Formation
• Mammary Gland Morphogenesis
• Lung Lobe Morphogenesis
• Response To Cholesterol
• Positive Regulation Of Epithelial To Mesenchymal Transition Involved In Endocardial Cushion Formation
• Lens Fiber Cell Apoptotic Process
• Positive Regulation Of Reactive Oxygen Species Metabolic Process