TGFβ and BMP signaling in cancer

Cancer progression is modulated by aberrant expression and secretion of cytokines at various stages. TGFβ and BMP belong to a superfamily of around 40 secreted cytokines that regulate a plethora of biological responses in normal as well as in cancer cells. Studies have shown that these molecules can regulate a large number of processes such as cell proliferation, apoptosis, senescence, differentiation, angiogenesis, immunosuppression, cell migration, and cancer metastasis. Recent studies have shed light into the molecular mechanisms and signaling networks that govern the effects of these pivotal pathways during cancer progression. Therefore it is becoming increasingly clear that unraveling the mechanistic complexity and clinical relevance of these pathways will greatly enhance our therapeutic efforts against tumor development and evolution of malignant cells. Most of the knowledge pertaining to the TGFβ superfamily of cytokines has been elucidated from studies regarding the TGFβ isoforms. There are three TGFβ isoforms, TGFβ1, TGFβ2, and TGFβ3, which are initially synthesized as inactive 75-kDa homodimeric pro-proteins, known as pro-TGFβ. These propeptides, referred to as the latency-associated proteins (LAPs), are part of the TGFβ large latent complex (LLC) which consists of LAPs and latent TGFβ binding proteins (LTBPs) assembled together by the formation of disulfide bonds between cysteine residues [1–3]. LTBPs are members of the LTBP/fibrillin protein family, which consists of fibrillin-1, 2, and 3 as well as LTBP-1, 2, 3, and 4. Out of these proteins, LTBP-1, 3, and 4 have the unique ability to bind LAP through the third of their four 8-cystein domains [4]. The remaining cysteine domains are likely to localize LTBPs to the extracellular matrix (ECM) [5]. As a part of the LLC, TGFβ remains in an inactive form. In this state, LAPs form a non-covalent, high-affinity association with TGFβ preventing the receptor–ligand interaction [6]. LLC is primarily localized at the matrix via covalent association of the N-terminal region of LTBPs with ECM proteins [7]. During the activation step, LAPs undergo conformational changes induced by thrombospondin-1 (TSP-1) [8, 9] and cleavage by furins and other convertases leading to the release of the mature 24-kDa TGFβ dimer [10, 11], which can bind to and activate TGFβ receptors resulting in the propagation of downstream signaling events.