ArfGAPs: Not Only for the Termination - Ras Superfamily Small G Proteins: Biology and Mechanisms 2 - page 252

et al. 2008 ), while the curvature of the COP-I-containing membranes, when
ArfGAP1 recognizes the curvature, determines the timing of hydrolysis of
GTP-Arf1, as earlier mentioned.
11.4 ADAP Subfamily
ADAP1 (ArfGAP with dual pleckstrin homology (PH) domains, also known as
centaurin ʱ 1, p42 IP4 , or PIP 3 BP) was purified from rat brain using a PI(3,4,5)P 3 -or
Ins(1,3,4,5)P 4 -affinity matrix (Hammonds-Odie et al. 1996 ). ADAP1 demonstrates
GAP activity toward Arf6, but not Arf1 (Venkateswarlu et al. 2004 ). ADAP2 was
identified as a protein closely related to ADAP1 and contains the same domain
structure (Whitley et al. 2002 ). ADAP1/2 possess a GAP domain at the N-terminus,
followed by two PH domains. The PH domains of ADAP1 bind to PI(3,4)P 2 and
PIP 3 (Venkateswarlu and Cullen 1999 ), while those of ADAP2 preferentially bind
to PI(3,4)P 2 (Whitley et al. 2002 ). These PH domains act to recruit ADAP1/2 to the
plasma membrane from the cytosol in a PI3 kinase-dependent manner
(Venkateswarlu et al. 2004 , 2007 ). It has been reported that such PI3 kinase-
dependent recruitment of ADAP1 to the plasma membrane is necessary to block
Arf6-dependent actin remodeling (Venkateswarlu et al. 2004 ).
ADAP1 is mainly expressed in the brain, whereas ADAP2 has a broad tissue
distribution, including the heart, skeletal muscle, and adipocytes but not the brain
(Whitley et al. 2002 ). The restricted distribution and high expression of ADAP1 in
the brain indicates that ADAP1 is vital for neuronal functions.
Regarding their involvement in neurological disease, ADAP1 expression is
increased in the neuritic plaques of Alzheimer's disease patients (Reiser and
Bernstein 2002 ), while ADAP2 gene deletion has been found in a majority of
neurofibromatosis type I patients (Jenne et al. 2000 ).
11.5 SMAP Subfamily
Stromal membrane-associated protein-1 (SMAP-1) was identified in mice as a type
II membrane protein (Sato et al. 1998 ). SMAP1 preferentially exhibits GAP activity
toward Arf6, while its isoform SMAP2 acts on Arf1 (Natsume et al. 2006 ). SMAP1/
2 contain a GAP domain and a clathrin interaction motif (LLGLD), which binds
both clathrin heavy chains and CALM, a clathrin assembly protein. SMAP1 is
diffusely located within the cytoplasm and colocalizes with AP-2, while SMAP2 is
found bound to endosomes and colocalizes with AP-1 and EpsinR, which are
adaptor proteins responsible for selecting cargo proteins. SMAP1 is involved in
Arf6-specific vesicle trafficking, but not Arf6-mediated actin remodeling, and
regulates clathrin-dependent endocytosis of the transferrin receptor and
E-cadherin. SMAP2 regulates Arf1-dependent retrograde transport of TGN38/46