Arf-like protein 4D

ADP-ribosylation factor (Arf)-like protein 4D (ARL4D) is a member of the Arf-like family of small GTPases. The protein sequence and primary structure of ARL4D are quite similar to those of other ARF/ARL molecules; however, its function within the cell remains unclear. Human ARL4 mRNA is highly expressed in testis, esophagus, uterus and kidney. Mouse Arl4d mRNA is predominantly detected in the liver and its expression is developmentally regulated. Given the high degree of amino-acid similarity between ARL4D and other ARFs, the function of ARL4D is assumed to depend on tightly regulated guanine nucleotide binding. ARL4D and its close homologs ARL4A and ARL4C differ from other members of the ARF GTPase protein family in that they possess a basic carboxy-terminal bipartite nuclear localization signal that interacts with importin-α. Indeed, immunolocalization studies have shown that ARL4D localizes to the nucleus and interacts with heterochromatin protein 1α (HP1α), suggesting a potential role in nuclear function. In addition to its nuclear localization, ARL4D was also detected at the plasma membrane. ARL4D recruits the cytohesin/ARNO family of ARF guanine nucleotide exchange factors to the plasma membrane through an interaction with the C-terminal pleckstrin homology and polybasic C domains of cytohesin-2/ARNO. ARL4D-induced translocation of ARNO to the plasma membrane results in activation of ARF6 and loss of actin stress fibers, and a reduction ARL4D levels suppresses cell migration activity. These observations indicate that a coordinated GTPase cascade between ARL4 and ARF6 is involved in cytoskeletal alterations and cell migration by regulating the plasma membrane localization of cytohesin-2/ARNO. Recently, this ARL4D-cytohesin-2/ARNO-ARF6 signaling cascade was shown to regulate valproic-acid-induced neurite outgrowth.