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Description

Cells respond to their environment in many different ways through intracellular signaling. The TGFbeta pathway plays a central role in a number of normal cellular processes including proliferation, differentiation, apoptosis, migration, adhesion, immune response and other functions in most cells. Although the TGFbeta pathway regulates a wide range of processes, the pathway is fairly simple. TGFbeta dimers bind to TGFbeta Type II Receptor which recruits and phosphorylates TGFbeta Type I Receptor. The Type I Receptor then recruits and phosphorylates SMAD2/3, which then binds to SMAD4 and forms a complex that enters the cell nucleus where it acts as a transcription factor for various genes. TGFbeta Receptor activates the SMAD-dependent canonical pathway, as well as SMAD-independent non-canonical pathways, such as PI3K/Akt, ERK, JNK, and p38. Aberrant TGFbeta signaling is involved in the development of multiple diseases, including hematological malignancies such as leukemia, and impaired wound healing, neurodegenerative diseases, developmental disorders and pulmonary hypertension. Loss-of-function mutations promote tumorigenesis by suppressing the immune system and the epithelial mesenchymal transition (EMT), although TGFbeta signaling has also been implicated in tumor inhibition. Immune cells such as B cells, T cells, dendritic cells and macrophages secrete TGFbeta, which downregulates their proliferation, differentiation and activation by other cytokines. Consequently, modifications in TGFbeta signaling have been linked to autoimmune and inflammatory diseases and cancer.