Together, Smad and non-Smad signaling pathways modulate cellular functions. Although the canonical Smad-dependent pathway mediates TGF-ОІ signaling, TGF-ОІ signaling is also initiated by Smad-independent signaling pathways, such as Erk, JNK, and p38 MAPK kinase pathways.

By associating with transcription factors, Smad complexes regulate the expression of target genes. Phosphorylation allows Smad 2/3 proteins to form heteromeric complexes and allows Smad 4 proteins to be translocated into the nucleus. After phosphorylation by TОІRII, TОІRI subsequently propagates the signal through phosphorylation of Smad 2/3 proteins. Dimerized TGF-ОІ exerts its functions by binding to type II receptor (TОІRII) serine/threonine kinases, followed by subsequent recruitment of type I receptors (TОІRI) on the cell surface. The proteolytic processing controls the bioavailability of active TGF-ОІs by releasing TGF-ОІ into intercellular spaces. The latent complex forms a multiprotein complex with integrins and extracellular matrix (ECM) proteins and retains TGF-ОІs in the inactive form. The LAP stays associated with the remaining domain and forms a latent complex.

Subsequently, the LAP is removed by the convertase family of endoproteases, producing a mature homodimer protein. Thus, TGF-ОІ1, ОІ2, and ОІ3 are synthesized as precursors comprising a propeptide (also named latency associated peptide (LAP)) and the mature domain. All levels of the TGF-ОІ signaling pathway are optimized for modulating TGF-ОІ family signal transduction. Three mammalian isoforms of TGF-ОІ, namely TGF-ОІ1, ОІ2, and ОІ3, are encoded by different genes, but they function through the same signaling system. Furthermore, impairment in the regulation of the TGF-ОІ signaling pathway may cause a broad range of illnesses, such as cardiovascular disease, tissue fibrosis, cancer, and congenital diseases. Through protein kinase receptors and Smad mediators, transforming growth factor-ОІ (TGF-ОІ) is involved in a wide range of biological processes such as embryonic development, morphogenesis, immune regulation, cell differentiation, wound healing, and inflammation. Finally, we review future challenges and provide future prospects in this field. Second, we highlight key role(s) of myosin motor-mediated protein trafficking and membrane domain segregation in the modulation of the TGF-ОІ signaling pathway. In this review, we present a brief overview of the current knowledge of the TGF-ОІ signaling pathway and the molecular components that comprise the core pathway as follows: ligands, receptors, and Smad mediators. Current models do not fully explain how membrane traffic forms a bridge between TGF-ОІ and the downstream effectors that produce its functional responsiveness, such as cell migration. Unconventional myosins modulate the spatial organization of endocytic trafficking and tether membranes or transport them along the actin cytoskeletons. Actin and unconventional myosin have crucial roles in subcellular trafficking of receptors research has also revealed a growing number of unconventional myosins that have crucial roles in TGF-ОІ signaling. These findings originate from the pivotal function of TGF-ОІ in development, cell proliferation, tumor metastasis, and many other processes essential in malignancy. Recent findings have revealed the role of membrane traffic in the signaling of transforming growth factor-ОІ (TGF-ОІ).

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