LRRC33 is a novel binding and potential regulating protein of TGF-β1 function in human acute myeloid leukemia cells

Abstract

Transforming growth factor‑β1 (TGF-β1) is a versatile cytokine. It has context-dependent pro- and anti-cell proliferation functions. Activation of latent TGF-β1 requires release of the growth factor from pro-complexes and is regulated through TGF-β binding proteins. Two types of TGF-β binding partners, latent TGF-β-binding proteins (LTBPs) and leucine-rich-repeat-containing protein 32 (LRRC32), have been identified and their expression are cell specific. TGF-β1 also plays important roles in acute myeloid leukemia (AML) cells. However, the expression of LTBPs and LRRC32 are lacking in myeloid lineage cells and the binding protein of TGF-β1 in these cells are unknown. Here we show that a novel leucine-rich-repeat-containing protein family member, LRRC33, with high mRNA level in AML cells, to be the binding and regulating protein of TGF-β1 in AML cells. Using two representative cell lines MV4-11 and AML193, we demonstrate that the protein expression of LRRC33 and TGF-β1 are correlated. LRRC33 co-localizes and forms complex with latent TGF-β1 protein on the cell surface and intracellularly in these cells. Similar as in other cell types, the activation of TGF-β1 in MV4-11 and AML193 cells are also integrin dependent. We anticipate our study to be a starting point of more comprehensive research on LRRC33 as novel TGF-β regulating protein and potential non-genomic based drug target for AML and other myeloid malignancy.

TGF‐β as a driver of fibrosis: physiological roles and therapeutic opportunities

“…GARP is also expressed by endothelial cells and fibroblasts [63]. The GARP‐related LRRC33 also associates with latent TGF‐β1 and similarly controls TGF‐β1 latency and activation in other cell types, including myeloid cells [64,65], while the related LRRC15, expressed by stromal fibroblasts of carcinomas [66], may similarly control cell‐associated TGF‐β1 retention. The expression of these LRRC proteins in fibrosis has not been characterized.…”

Role and clinical significance of TGF‑β1 and TGF‑βR1 in malignant tumors (Review)

“…The TGF-β signaling pathway serves an important role in cell cycle regulation, growth and development, differentiation, ECM synthesis, hematopoiesis, chemotaxis and immune response ( 1 - 3 ). In recent years, studies on malignant tumors have revealed that TGF-β1 and TGF-βR1 may serve important roles in tumor occurrence and development, including in promoting tumor angiogenesis, invasion, EMT and immune escape ( 4 , 5 , 197 ). Increased expression levels of miR-331-3p ( 22 ), HnRNP K ( 146 ), Sema4C ( 157 ) and p68 ( 156 ), and the activation of the JAK/STAT3/Twist ( 111 ), NF-κB ( 127 ) and TGF-β signaling pathways in tumor cells can promote proliferation, migration and EMT through the action of TGF-β1 or TGF-βR1.…”

“…This process may provide an effective therapeutic target for improving normal hematopoiesis in AML ( 142 ). Ma et al ( 5 ) found that leucine-rich repeat containing protein 33, a cell membrane-associated protein, formed complexes with pro-TGF-β1 and regulated the function of TGF-β1 in AML cells and other myeloid malignancies. However, to the best of our knowledge, no studies have investigated the mechanism of TGF-βR1 in leukemia.…”

“…Transforming growth factor-β (TGF-β) is a complicated polypeptide that exerts essential effects on cell cycle regulation, growth and development, differentiation, extracellular matrix (ECM) synthesis, hematopoiesis, chemotaxis and the immune response ( 1 - 3 ). TGF-β1 and TGF-β receptor 1 (TGF-βR1) serve important roles in the TGF-β family, and have irreplaceable effects on cell reproductive capacity, growth, wound regeneration and immunological reactions ( 4 , 5 ). Almost all cells in the body, not only the epithelium and lymphocytes, but also the stroma, cellular immunity and endotheliocytes, are associated with tumor occurrence and development ( 6 , 7 ).…”

Biallelic mutations in NRROS cause an early onset lethal microgliopathy

“…NRROS is a leucine-rich repeat containing transmembrane protein localized to the endoplasmic reticulum, and preferentially expressed in myeloid cells. Reported functions include the regulation of reactive oxygen species (ROS) production through control of NOX2 stability [12], responsiveness of Toll-like receptor signaling [19], and processing/activation of transforming growth factor (TGF)-β via physical interactions with the latent complex [10,15]. NRROS expression is restricted to microglia within the CNS parenchymal compartment in humans and mice.…”