Presentation Title

Role of TGFβ-Type I Receptor ALK5 in Cartilage Development

Faculty Mentor

Karen M. Lyons

Start Date

17-11-2018 8:30 AM

End Date

17-11-2018 10:30 AM

Location

CREVELING 99

Session

POSTER 1

Type of Presentation

Poster

Subject Area

biological_agricultural_sciences

Abstract

Members of the Transforming Growth Factor-beta (TGFβ) superfamily of proteins play vital roles in cartilage development. Activin receptor-like kinase 5 (ALK5) is the TGFβ type I receptor that activates TGFβ signaling. However, the functions of ALK5 in cartilage and mechanisms by which it mediates its effects are unclear. Our prior work illustrated cartilage-specific ALK5 ablation in mice resulted in severe chondrodysplasia. Moreover, Bone Morphogenetic Protein (BMP) signaling was elevated in mutant cartilage. Because ALK5 can form physical complexes with BMP receptor ALK1, we hypothesized that ALK5 normally antagonizes BMP signaling transduced by ALK1; loss of ALK5 would therefore lead to elevated BMP signaling through ALK1. Our finding that double knockout ALK5/ALK1 mice show nearly complete rescue of the ALK5 phenotype supports this hypothesis. We therefore performed western blots and co-immunoprecipitations to study receptor interactions. Activin receptor types IIA (ActRIIA) and IIB (ActRIIB) are BMP type II receptors. Our data show that the majority of ALK5 in cartilage is present in ALK5/ActRIIB complexes, and most ALK1 in cartilage is present in ALK1/ActRIIA complexes. Loss of ALK5 leads to a redistribution of ActRIIB into ALK1/ActRIIB complexes, which have considerably greater affinity for certain BMP ligands than do ALK1/ActRIIA complexes. Our studies thus suggest that rather than acting as a transducer of TGFβ signals, the major function of ALK5 is to suppress BMP signaling pathways. Understanding how the relative output of TGFβ and BMP pathways is controlled at the level of receptor utilization is essential for therapeutic intervention for cartilage regeneration.

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Nov 17th, 8:30 AM Nov 17th, 10:30 AM

Role of TGFβ-Type I Receptor ALK5 in Cartilage Development

CREVELING 99

Members of the Transforming Growth Factor-beta (TGFβ) superfamily of proteins play vital roles in cartilage development. Activin receptor-like kinase 5 (ALK5) is the TGFβ type I receptor that activates TGFβ signaling. However, the functions of ALK5 in cartilage and mechanisms by which it mediates its effects are unclear. Our prior work illustrated cartilage-specific ALK5 ablation in mice resulted in severe chondrodysplasia. Moreover, Bone Morphogenetic Protein (BMP) signaling was elevated in mutant cartilage. Because ALK5 can form physical complexes with BMP receptor ALK1, we hypothesized that ALK5 normally antagonizes BMP signaling transduced by ALK1; loss of ALK5 would therefore lead to elevated BMP signaling through ALK1. Our finding that double knockout ALK5/ALK1 mice show nearly complete rescue of the ALK5 phenotype supports this hypothesis. We therefore performed western blots and co-immunoprecipitations to study receptor interactions. Activin receptor types IIA (ActRIIA) and IIB (ActRIIB) are BMP type II receptors. Our data show that the majority of ALK5 in cartilage is present in ALK5/ActRIIB complexes, and most ALK1 in cartilage is present in ALK1/ActRIIA complexes. Loss of ALK5 leads to a redistribution of ActRIIB into ALK1/ActRIIB complexes, which have considerably greater affinity for certain BMP ligands than do ALK1/ActRIIA complexes. Our studies thus suggest that rather than acting as a transducer of TGFβ signals, the major function of ALK5 is to suppress BMP signaling pathways. Understanding how the relative output of TGFβ and BMP pathways is controlled at the level of receptor utilization is essential for therapeutic intervention for cartilage regeneration.