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FLASH GENE

Symbol

APPL1

contributors: mct/pgu - updated : 27-02-2013

HGNC name	adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1
HGNC id	24035

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	3p14.3      Physical location : 57.261.764 - 57.307.496
Synonym name	adaptor protein containing pH domain, PTB domain and leucine zipper motif
	signaling adaptor protein DIP13alpha
	adaptor molecule interacting with the oncoprotein AKT2
	DCC-interacting protein 13-alpha
Synonym symbol(s)	APPA, DIP13alpha, KIAA1428, APPL

DNA

TYPE	functioning gene
STRUCTURE	45.74 kb     22 Exon(s)

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_012096 22 - 6061 NP_036228 - 709 - 2008 18455989

EXPRESSION

Type	ubiquitous

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Endocrine pancreas       highly Hearing/Equilibrium ear inner cochlea   highly Lymphoid/Immune lymph node       highly Nervous brain           spinal cord       highly Reproductive female system ovary     highly   male system prostate       Respiratory respiratory tract trachea     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / Hematopoietic bone marrow       Muscular striatum skeletal   highly Nervous central

cell lineage

cell lines

fluid/secretion

at STAGE

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a PH (pleckstrin homology) domain
	one PID domain
	a PTB domain and leucine zipper

conjugated

PhosphoP

mono polymer

homomer , heteromer , oligo

HOMOLOGY

interspecies

homolog to murine Appl1 (98.3pc)

Homologene

FAMILY

CATEGORY

adaptor , regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm,organelle,membrane
	intracellular,cytoplasm,organelle,endosome
	intracellular,cytoplasm,cytosolic
	intracellular,nucleus
text	localized in endosomes but also capable of nucleocytoplasmic shuttling

basic FUNCTION	recruiting kinases AKT2 and PIK3 to the cell membrane
	protein serine/threonine kinase, mediating the DCC apoptotic pathway
	selectively regulates apoptosis during development by controlling AKT1 signaling
	may be involved in cell division
	acting as a critical regulator of the crosstalk between adiponectin signaling and insulin signaling pathways
	may suppress androgen receptor transactivation via potentiating AKT1 activity
	mediates AKT1 substrate specificity and cell survival in vertebrate development
	its overexpression has a proapoptotic effect
	activator of beta-catenin/TCF-mediated transcription
	may act as a scaffold that modulated Rab5-associated signaling endosomal membrane by its ability to undergo domain-mediated oligomerizatio, membrane targeting and phosphoinositide binding
	recruitment of APPL1 to ubiquitin-rich aggresomes in response to proteasomal impairment
	APPL1 and APPL2 appear to play important roles in cargo trafficking and signal transduction
	required for EGFR signaling by regulation of EGFR stabilities through inhibition of RAB5A
	role in regulating cell migration and adhesion turnover through a mechanism that depends on SRC and AKT1
	positive regulator of transcriptional activity of NFKB under basal but not TNF-stimulated conditions
	APPL1 synergized with TRAF2 to induce NFKB activation, and both proteins were necessary for this process and function upstream of the IKK complex
	plays a critical role in regulating adiponectin and insulin signaling

CELLULAR PROCESS	cell life, proliferation/growth

PHYSIOLOGICAL PROCESS

PATHWAY

metabolism

signaling

signal transduction

intracellular signaling cascade

a component	associating with the nuclear co-repressor complex NuRD, containing enzymatically acitve HDAC2
	APPL1, an interacting partner of AKT1, forms complexes with CDON and BOC in differentiating myoblasts

INTERACTION

DNA

RNA

small molecule

protein	binding to the oncoprotein AKT2 and PI3 kinase catalytic subunit p110alpha
	binding to DCC
	interacting with SSNA1
	interacts with adiponectin receptors and the interaction is stimulated by adiponectin
	interacts with transmembrane receptors and AKT1
	binding partner for the NTRK1-interacting protein GIPC1
	interacting with GIPC1 (GIPC1 and APPL1 play a role in NTRK1 function and suggest that a population of endosomes bearing a complex of APPL1, GIPC1, and activated NTRK1 may transmit NGF signals)
	binding to RAB5A
	directly interact with TRAF2, an adaptor protein known to activate canonical NFKB signaling
	function as a downstream effector of EGF-initiated signaling

cell & other

REGULATION

Phosphorylated by

PRKCA (PRKCA is the kinase mediating ER stress-induced phosphorylation of APPL1 at Ser(430)

Other	phosphorylated by ATM or ATR
	cellular levels of HDAC1 can regulate the extent of APPL1-NuRD interaction which in turn regulates the nucleoplasmic distribution of APPL1

ASSOCIATED DISORDERS

corresponding disease(s)

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional     --over   caused developmental delay and with high penetrance a number of dysmorphic phenotypes, such as severely swollen yolk extension, slightly swollen telencephalon, blown-up blood island and, later in development, sharp kinks in body axes

Susceptibility

Variant & Polymorphism

Candidate gene
Marker
Therapy target
	System Type Disorder Pubmed cancer     good candidate to target for the treatment of cancers caused by dysregulation of EGF signaling cancer     regulatory function of APPL1 on Akt signaling and its mediated substrate specificity discovered here may therefore render APPL1 a particularly interesting target for cancer therapy

ANIMAL & CELL MODELS