ABSTRACT
The serine-threonine kinase receptor-associated protein (STRAP) was initially identified as a putative inhibitor of the canonical TGF-beta signaling pathway. Because the Smad-dependent TGF-beta pathway negatively regulates cellular growth, early functional studies suggested that STRAP behaves as an oncogene. Indeed, a correlation between STRAP overexpression and various cancers has been identified. With the emergence of new studies on the biological function of STRAP, it is becoming clear that STRAP regulates several distinct cellular processes and modulates multiple signaling pathways. While STRAP itself does not possess enzymatic activity, it appears that STRAP influences biological processes through associations with cellular proteins. In this review, we will describe the TGF-beta-dependent and -independent functions of STRAP and provide a context for the significance of STRAP activity in the development of cancer.
Subject(s)
Neoplasms/physiopathology , Proteins/physiology , Transforming Growth Factor beta/physiology , Adaptor Proteins, Signal Transducing , Animals , Calmodulin-Binding Proteins/physiology , Epithelial-Mesenchymal Transition/drug effects , Humans , MAP Kinase Kinase Kinase 5/metabolism , Mice , NM23 Nucleoside Diphosphate Kinases/metabolism , Phosphatidylinositol 3-Kinases/physiology , Protein Serine-Threonine Kinases/metabolism , Pyruvate Dehydrogenase Acetyl-Transferring Kinase , RNA, Messenger/metabolism , RNA-Binding Protein EWS , RNA-Binding Proteins/physiology , Signal Transduction , Smad Proteins/physiology , Smad Proteins, Inhibitory/physiology , Tumor Cells, CulturedABSTRACT
The signaling pathway mediated by transforming growth factor-beta (TGF-beta) participates in various biologic processes, including cell growth, differentiation, angiogenesis, apoptosis, and extracellular matrix remodeling. In the context of cancer, TGF-beta signaling can inhibit tumor growth in early-stage tumors. However, in late-stage tumors, the very same pathway promotes tumor invasiveness and metastasis. This paradoxical effect is mediated through similar to mothers against decapentaplegic or Smad protein dependent and independent mechanisms and provides an opportunity for targeted cancer therapy. This review summarizes the molecular process of TGF-beta signaling and the changes in inhibitory Smads that contribute to lung cancer progression. We also present current approaches for rational therapies that target the TGF-beta signaling pathway in cancer.
Subject(s)
Carcinoma, Non-Small-Cell Lung/metabolism , Lung Neoplasms/metabolism , Signal Transduction , Smad Proteins, Inhibitory/physiology , Transforming Growth Factor beta/metabolism , Animals , Carcinoma, Non-Small-Cell Lung/pathology , Humans , Lung Neoplasms/pathologyABSTRACT
Between 2 and 10 years of age, the developing craniofacial skeleton poses a significant reconstructive challenge. Local autogenous bone is largely unavailable, distant bone grafts are fraught with significant morbidity and limited yield, and alloplastic materials are incompatible with the growing calvarium and facial skeleton. Bone morphogenetic protein (BMP) 2, a member of a class of proteins first noticed in the 1960s to promote bone deposition in soft tissues, offers a potential solution to the bone shortage historically faced by the pediatric craniofacial surgeon. A review of English language literature was conducted from the 1960s to the present.Attention was focused on BMP-2's osteoinductive mechanism, basic science and translational laboratory findings, and multidisciplinary clinical experiences. Bone morphogenetic protein 2 has been embraced by spine surgeons, is gaining in popularity for long-bone repair, and is making its way into the plastic surgery literature. Bone morphogenetic protein 2 may provide a basis for an off-the-shelf tissue-engineered bone construct that is compatible with the growing craniofacial skeleton while free from the morbidities of distant graft harvest. Questions remain, however, regarding the safety and efficacy of this compound in the context of pediatric craniofacial surgery. In an effort to facilitate the clinician's risk-benefit analysis of this emerging technology, we present a primer on the basic science of BMP-2, a discussion of possible morbidities associated with its use, a review of laboratory and clinical trials with this substance to date, and an analysis of strategies to maximize its efficacy in craniofacial surgery.
