GPRASP (GPCR-associated sorting protein)/ARMCX (ARMadillo repeat-Containing proteins
on the X chromosome) family is composed of 10 proteins, whose genes are located on a small locus
of the X chromosome except one. They possess at least two armadillo-like repeats on their carboxylterminal
homologous sequence, but they can be subdivided on specific sequence features. Subfamily 1
(GPRASP1, GPRASP2, GPRASP3, ARMCX4 and ARMCX5) displays additional repeated motifs while
a mitochondrial targeting transmembrane domain is present in subfamily 2 (ARMC10, ARMCX1,
ARMCX2, ARMCX3 and ARMCX6). Although their roles are not yet fully understood, the recent identification
of several interacting partners has shed new light on the processes in which GPRASP/ARMCX
proteins are implicated. Among the interacting partners of proteins from subfamily 1, many are GPCRs.
GPRASP1 binds trafficking proteins, such as Beclin2 and the Dysbindin-HRS-Gαs complex, to participate
in GPCR post-endocytic sorting. Moreover, in vitro as well as in vivo experiments indicate that
GPRASP1 is a critical player in the adaptive responses related to chronic treatments with GPCR agonists.
GPRASP2 seems to play a key role in the signaling of the hedgehog pathway in the primary cilium
through a Smoothened-GPRASP2-Pifo complex. Identified small compound inhibitors of this complex
could treat drug-resistant smoothened derived cancer forms. Deletion of GPRASP2 in mice causes neurodevelopmental
alteration and affects mGluR5 regulation, reflected by autism-like behavior. Several
members of subfamily 2, in complex with TRAK2 and MIRO, are involved in the trafficking of mitochondria
in axons and in the regulation of their size and division, influencing the cell cycle. The essential
role of GPRASP/ARMCX proteins in cellular physiology is supported by human cases of deletions,
causing male neonatal lethality by pulmonary delayed development, dysmorphic face, and psychiatric
and intellectual impacts in females.