Four and a half LIM domains protein 1 can be as a double-edged sword in cancer progression

Figures

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  Figure 1. Structure and homology of FHL1 proteins. FHL1A contains four complete and an N-terminal half LIM domain. FHL1B contains the N-terminal three and a half LIM domains identical to FHL1A. However, in this case, the C-terminus is replaced by three nuclear localization signals (NLS), a nuclear export sequence (NES), and a binding site for RBP-Jκ. FHL1C comprises the N-terminal two and a half LIM domains identical to FHL1A and FHL1B, followed by a C-terminal RBP-Jκ-binding domain.

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  Figure 2. FHL1 functions as a tumor suppressor. FHL1 interacts with Smad2, Smad3, and CK1δ in hepatocellular carcinoma cells, and enhances phosphorylation of Smad proteins and nuclear translocation of Smad4 to regulate downstream target genes, such as p21 and c-myc. In human breast cancer cells, FHL1 interacts directly with ERα or inhibits AKT to decrease transcriptional activity of ERα, resulting in suppression of estrogen target gene expression, including pS2 and cathepsin D52. Furthermore, RIP140 cooperates with ER to inhibit estrogen signaling and estrogen-responsive target gene transcription. FHL1 inhibits HIF-1 transcriptional activity by competing with HIF-1 for binding to the co-activators, p300/CBP48, or blocking HIF1α-HIF1β heterodimerization. Levels of G1 and G2/M phase-related proteins, including cyclin A, B1, D, and E, are suppressed by FHL1 to mediate G1 and G2/M cell cycle arrest in lung cancer cells.

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  Figure 3. Phosphorylated FHL1 functions as a tumor promoter. Src interacts with and phosphorylates FHL1, which immediately trigrers translocation into the nucleus. Phosphorylated FHL1 binds to and cooperates with nucelar transcription factor BCL, promoting tumor cell growth. However, in the presence of excessive cellular Kindlin-2, FHL1 is recruited to focal adhesion sites and forms a complex with Kindlin-2 and Src. Interactions between Src and FHL1 and subsequent Src-induced phosphorylation of FHL1 are suppressed in this state, which maintains the tumor suppressive role of FHL1.