previously , we identified a brain specific nuclear gtpase called pike , which binds pi 3-kinase and enhances its kinase activity .
ngf treatment elicits the membrane - associated 4.1n nuclear translocation and binds pike , which was initially identified as a 4.1n binding partner in a yeast two - hybrid screening .
the binding of 4.1n to pike prevents its interactions with nuclear pi 3-kinase , leading to diminish the activation of pi 3-kinase by ngf 1 .
pike gtpase is activated by nuclear translocated phospholipase c-1 ( plc-1 ) , which acts as a guanine nucleotide exchange factor ( gef ) for pike .
this action is not dependent on plc-1 's lipase activity but appears instead to involve its sh3 domain 2 .
recently , we have identified and cloned a few isoforms of pike : pike - l and pike - a . both of them contain an arfgap domain and two ankyrin repeats domains .
the c - terminal protein structure resembles that of centaurin family , which are gtpase  activating proteins ( gaps ) for arfs or have homology to arfgaps and arf effectors 3 , 4 . in rat brain and hippocampal neurons
, pike - l physiologically binds to homer , an adaptor protein known to link metabotropic glutamate receptors ( mglur i ) to multiple intracellular targets including the inositol 1,4,5 trisphosphate ( ip3 ) receptor .
the activation of mglur i by its agonists enhances formation of an mglur i - homer - pike - l complex leading to activation of pi 3-kinase activity and prevention of neuronal apoptosis 5 .
pike - a differs from pike - l and -s by lacking the n - terminal proline - rich domain ( prd ) , which binds pi 3-kinase .
interestingly , pike - a directly binds to activated akt but not pi 3-kinase in a guanine nucleotide - dependent way and stimulates the kinase activity of akt .
pike - a is co - amplified with cdk4 in a variety of human cancers .
the overexpressed pike - a enhances akt activity , promotes cancer cell invasion and prevents apoptosis 6 .
mounting evidence demonstrates that akt is a crucial regulator of diverse cellular processes and contributes to cancer progression .
activation of akt is essentially dependent on pi 3-kinase signaling . nevertheless , pike - a - mediated akt activation is independent of pi 3-kinase .
therefore , pike - a provides a new mechanism whereby growth factors and other cellular stimuli regulate akt , and functions as an oncogenic effector of cell invasion . here
, we discuss the recent advances in biochemical and molecular studies and future directions that might further our understanding of the roles of nuclear pi 3-kinase and pike family .
pike - s comprises 753 residues , containing three proline - rich domains ( prd ) in the n - terminus , followed by a gtpase domain and a partial pleckstrin homology ( ph ) domain in the c - terminus .
ngf treatment of pc12 cells activates pike gtpase with peak at 30 min and decays after 1 h. pike - s binds nuclear pi 3-kinase in a gtp - dependent manner .
pike - s activates pi 3-kinase depending on the presence of its two subunits with pike - s being able to bind independently to each of the two subunits p85 and p110 .
transfected by itself , p110 lacks catalytic activity but acquires it following co - transfection with p85 .
pike - s can activate pi 3-kinase only when both p110 and p85 are expressed , not with p110 alone 1 .
normally , gtpases cycles between the active , gtp - bound and inactive , gdp - bound states 7 , 8 .
guanine - nucleotide - exchange factors ( gefs ) act as positive regulators that promote release of gdp and consequent formation of the active gtp - bound state , whereas gtpase - activating proteins ( gaps ) act as negative regulators , stimulating the intrinsic gtpase activity to generate the inactive gdp - bound form .
indeed , plc-1 binding to pike involves the sh3 domain of plc-1 interacting with the prd of pike - s 2 .
we have demonstrated that plc-1 acts as a physiologic guanine nucleotide exchange factor ( gef ) for pike - s .
this gef activity is mediated by the sh3 domain with phospholipase catalytic activity not required .
moreover , the sh3 domain but not phospholipase catalytic activity of plc-1 is necessary for its mitogenic actions , probably through activating the nuclear pi 3-kinase 2 .
the activated plc-1 translocates to the plasma membrane and triggers the hydrolysis of phosphatidylinositol 4,5-bisphosphate ( pip2 ) into two second messengers , inositol 1,4,5-triphosphate ( ip3 ) and diacyglycerol ( dag ) , which regulate the intracellular caand activation of protein kinase c respectively .
plc-1 does not possess any known nuclear localization signal and predominantly localizes in the cytoplasm .
nevertheless , it has been reported to be present in the nucleus 9 - 12 .
it has been shown that plc-1 localizes to the nucleus of highly transformed and proliferating cell lines ( a431 , hela , mouse hepatoma mh 22a , rat zajdela ascitic hepatoma ) but not to the nucleus of primary embryo skin or lung fibroblasts , where the enzyme is primarily cytoplasmic .
differential subcellular localizations in normal or highly transformed cell lines may reflect the degree of transformation of the cell type or phase of the cell cycle 10 .
this finding is consistent with the observation of an increased amount of plc-1 in nuclei of 22 h regenerating rat liver , suggesting a relationship between the s - phase of the cell cycle and intranuclear localization of plc-1 13 .
pi 3-kinase is a key regulator of many cellular processes including cell proliferation , survival , motility , vesicular trafficking and carbohydrate metabolism .
pi 3-kinase is activated by both receptor tyrosine kinases ( rtk ) and cytoplasma membrane associated gtpase proteins .
the activated pi 3-kinase generates the critical second messengers : the d-3 position phosphorylated phosphoinositides , which bind to the pleckstrin homology domain ( ph ) of numerous signaling molecules including phosphoinositol - dependent kinase 1 ( pdk1 ) , akt / pkb and plc-1 , etc .
while much has been learned about pi 3-kinase signal transduction in the cytoplasm , almost nothing is known about it in the nucleus .
previous studies show that pi 3-kinase also occurs in the nucleus 1 , 14 - 19 .
stimulation of cells with ngf activates nuclear pi 3-kinase with nuclear accumulation of 3-phosphorylated phosphoinositide lipids 18 , 20 .
however , the physiological role of nuclear pi 3-kinase and its mediated signaling pathways remain obscure .
the interaction between pike - s and pi 3-kinase is gtp - dependent  like that between ras and pi 3-kinase 1 , 21 .
ngf treatment of pc12 cells activates pike and nuclear pi 3-kinase with peaks at 30 min , whereas ngf activates the cytoplasmic gtpases of the ras family as well as cytoplasmic pi 3-kinase much more rapidly with peak activity in 5 - 10 min 21 .
moreover , in dominant - negative pike - s ( k413as414n ) retrovirus infected pc12 cells , activation by ngf of nuclear pi 3-kinase is abolished , suggesting that pike - s is the major mediator of nuclear pi 3-kinase .
cytoplasmic pi 3-kinase activation requires activated receptor tyrosine kinases ( e.g. pdgfr , egfr , cd28 , etc . ) or gtpase proteins such as ras . however , none of these known pi 3-k activators are present in nucleus .
our discovery that the nuclear gtpase , pike , enhances nuclear pi 3-kinase activity indicates that pike - s may be the nuclear counterpart of ras .
the extreme n - terminus of pike - s associates with the c - terminal domain ( ctd ) of protein 4.1n , a neuronal isoform of the erythrocyte membrane cytoskeletal protein 4.1r .
therefore , activation of nuclear pi 3-kinase by pike is inhibited by the ngf - stimulated 4.1n translocation to the nucleus 1 .
plc-1 and pi 3-kinase share the same substrate pi ( 4,5 ) p2 , and both enzymes are concomitantly recruited to the plasma membrane and activated , where they mediate each other 's enzymatic activity .
several studies have suggested cross - talk between plc-1 and pi 3-kinase in the cytoplasm .
for example , pi ( 3,4,5 ) p3 generated by pi 3-kinase influences plc-1 membrane translocation and activation by binding to its ph domain and a c - terminal sh2 domain 22 , 23 , and activation of plc downregulates pi 3-kinase by at least two mechanisms : ( 1 ) inhibition of irs-1-associated pi 3-kinase ; and ( 2 ) acute activation of a ptdins ( 3,4,5 ) p3 5-phosphatase .
ngf elicits plc-1 nuclear translocation and acts as a gef for pike through it sh3 domain .
thus , the nuclear plc-1/pike / pi 3-kinase signaling pathway seems to be the extension of the cross - talk between the cytoplasmic plc-1 and pi 3-kinase .
pike - l was identified in searching databases for sequences that might resemble pike - s .
pike - l differs from pike - s in containing a 40 kda c - terminal extension which includes an arf - gap and two ankyrin repeats domains 5 .
pike - l and pike - s are alternatively spliced isoforms and brain - specific . however , whereas pike - s occurs in all brain regions examined , pike - l is uniquely absent from the cerebellum .
pike - s is exclusively nuclear , whereas pike - l occurs in multiple subcellular fractions and , by immunohistochemistry , is observed throughout the cell body and all neuronal processes 5 .
sequence analysis led to the discovery that pike - l binds to homer 1c , an adaptor protein localized to postsynaptic densities coupling cytoplasmic regions of group i coupling metabotropic glutamate receptors ( mglurs ) to inositol-1,4,5-trisphosphate receptors ( ip3rs ) as well as shank proteins 24 .
the mglurs comprise three groups : group i ( mglur 1 and 5 ) , group ii ( mglur 2 and 3 ) and group iii ( mglur 4 , 6 , 7 and 8) . via g proteins , group i receptors stimulate phospholipase  ( plc ) leading to the formation of ip3 and calcium mobilization .
by contrast , group ii and group iii receptors are negatively coupled to adenylyl cyclase 25 .
one particularly prominent action of group i mglurs is to protect neurons from apoptotic death 26 .
binding of mgluri with homer and thereby with pike - l occurs only with the group i class of mglurs , which are the only forms that contain the homer ligand pxxf motif .
amino acids 187 - 190 of pike - l are pkpf which corresponds to a domain recently appreciated as a consensus motif ( pxxf ) present in proteins that bind to the evh1 domain of homer 24 .
pike - l and homer 1c coprecipitate robustly , and the interaction is dependent upon the portion of pike - l containing the pkpf sequence .
mutation of proline-187 of pike - l abolishes binding of pike - l to homer 1c and provides a useful tool to analyze the importance of this binding in various signal cascades .
pike - l / homer 1c complex couples pi 3-kinase to metabotropic glutamate receptor 1 ( mglur1 ) , suggesting that mglur1 might activate pi 3-kinase separately from its well - known activation of phospholipase c. this pathway has been verified by the demonstration that mglur5 transfection of hek293 cells stimulates pi 3-kinase activity while mutants of mglur5 that do not bind homer fail to activate pi 3-kinase 5 . moreover , homer mutants that do not bind mglur5 block pi 3-kinase activation . in hippocampal cultures mglur
i activation increases pi 3-kinase activity , while infection with an adenovirus containing a dominant - negative form of pike - l blocks such activation .
delivery into hippocampal cultures of the homer - binding motif of pike as a dominant - negative , blocks mglur i stimulation of pi 3-kinase , while mutant peptides that do not bind homer have no effect .
finally , mglur i activation fails to stimulate pi 3-kinase in the cerebellum , a brain region that is devoid of pike - l .
prevention of neuronal apoptosis is a major action of group i mglurs , and this process appears to be mediated by pike - l and pi 3-kinase 5 . in hippocampal cultures mglur
i activation and pike - l transfection block the apoptotic effects of staurosporine and other agents .
by contrast , infection with a pike - l dominant - negative construct augments apoptosis , and a pike construct which can not bind homer prevents the anti - apoptotic actions of mglur activation .
additionally , mglur i activation does not block apoptosis in the cerebellum , which lacks pike - l .
pike - l may have other activities besides mediating actions of mglur i on pi 3-kinase and apoptosis .
some possibilities are suggested by the structure of pike - l , whose c - terminal region contains an arf - gap domain and two ankyrin repeats .
gtpases are typically activated by gap proteins , but whether the arf - gap domain functions as an internal gap for the gtpase activity of pike - l remains to be determined , though there are instances of arf - gap domains exerting such activity 27 .
mediation of anti - apoptotic actions is the only mglur i function thus far examined in connection with pike - l .
group i mglurs exert a variety of neuronal functions , influencing motor learning and coordination via cerebellar purkinje cells 28 and influencing long term potentiation in the hippocampus 29 .
in our evaluation of pike amplification in human glioblastoma multiforme , we have identified a third pike form ( pike - a ) , which was originally identified in the human genome sequencing effort as kiaa0167 30 , and was independently identified by liu and collaborators 27 . the chromosome 12q13 - 15 region is frequently amplified in human sarcomas and brain tumors 31 , 32 .
12q13 - 15 amplicon contains two separate core regions , one containing mdm2 and the other containing cyclin - dependent - kinase 4 ( cdk4 ) 32 , 33 .
gene structure analysis reveals that pike - a results from different transcription initiation site from that of pike - l and -s .
pike - a contains the gtpase , ph , arfgap and two ankyrin repeats domains present in pike - l but lacks the prd containing n - terminus , which binds protein 4.1n , pi 3-kinase and plc-1 .
fluorescent in - situ hybridization ( fish ) and northern blotting analysis reveal that pike gene is amplified in a variety of human sarcoma and brain tumor cell lines 6 .
unlike pike - l or -s , pike - a does not associate with pi 3-kinase , instead , it binds to active but not inactive akt .
truncation analysis demonstrates that gtpase and ankyrin repeats domains interact with partial catalytic and regulatory domains of akt .
binding by akt to purified recombinant gst - pike - a is evident in cells treated with the mitogenic stimulus igf-1 compared to untreated cells .
gtp--s and gdp--s strongly stimulate binding of activated akt and pike - a compared to faint binding in the absence of guanine nucleotide treatment 6 .
interestingly , dominant - negative pike - a - dn binds akt promiscuously even in cells not treated by growth factor igf-1 and , in treated cells , binding occurs even in the absence of guanine nucleotides .
pike - a strongly binds to active akt , indicating that akt phosphorylation might play a role in mediating its association with pike - a . in vitro akt
kinase assay demonstrates that pike - a substantially enhances akt activity , for which gtpase domain but not ankyrin repeats domain is responsible . to date , numerous pike binding proteins have been identified and are now depicted in figure 3 .
functional analysis of the interaction between pike - a and akt demonstrates that pike - a mediates invasion of cancer cells through akt .
two human glioblastoma cell lines , ln - z308 , in which pike - a is heavily overexpressed , and u87 mg that does not overexpress pike - a , were utilized to dissect the physiological consequence of pike amplification .
infection of u87 mg cells with an adenovirus containing wild - type pike - a elicits almost a doubling of invasive cell number .
only a modest increase occurs with the ln - z308 cells , presumably because endogenous pike - a is already highly expressed . in both ln - z308 and u87 mg cells ,
infection with pike - a - dn reduces cell invasion by about 50% compared with control cells .
thus , pike - a is a physiologic regulator of akt and an oncogenic effector of cell invasion 6 .
more recently , we show that overexpression of pike - a wild - type but not dominant - negative mutant prevents apoptosis through mediating akt activity .
collectively , these observations suggest that pike - a amplification contributes to cancer cell survival and progression by inhibiting apoptosis through upregulating akt 34 .
agap1/ggap1/kiaa1099 ( accession number ab029022 ) , m - rip ( accession number af359283 ) , and agap2/ggap2/kiaa0167 , we have now designated it as pike - a ( accession number d79989 ) , consist of the identical gene structure .
ggap1 and ggap2 share approximately 50% sequence homology , while ggap1 and mrip1 share 70% sequence homology at the amino acid level .
the complete protein sequences of this family encode an n - terminal ras - related gtpase domain , a ph domain , followed by a c - terminal gap domain and an ank repeat domain .
the gtpase domain in the ggap proteins reveals 60% homology to the ras family of gtpases .
identical to k - ras , agap2 is 42% similar and 28% identical to rab9 , and m - rip is 47% similar and 27% identical to h - ras 35 .
northern blotting analysis demonstrates that ggap1 mrna was found in most of the tissues although the level of expression is varied , with enriched expression in skeletal muscle , brain , placenta , and kidney .
most tissues contain two messages at 5 kb and 8.5 kb , while the peripheral blood leukocytes ( pbl ) have only one message with the size of 5.5 kb .
the expression of pike - a is highly enriched in the brain , heart , skeletal muscle , and immune tissues 27 , 32 .
northern blotting analysis of human brain regions reveals that a prominent band was found in cerebellum , cerebral cortex , occipital pole , frontal lobe , temporal lobe , and putamen for ggap1 and ggap2 ( pike - a ) , while low level of expression was detected in medulla and spinal cord for pike - a 27 .
subcellular localization reveals agap / ggaps are expressed in different cellular compartments . in transfected cos-7 cells ,
flag - tagged agap1/ggap1 staining occurs in the cytosol , possibly in the internal membrane systems , such as the endoplasmic reticulum ( er ) and the golgi apparatus . on the other hand , the flag - tagged ggap2/pike - a was stained in both the cytoplasm and the nucleus
this observation is consistent with the subcellular distribution of amplified pike - a in human glioblastoma cells 6 .
furthermore , cells overexpressing agap1/ggap1 are more flat and have much more lamellipodia than control cells .
in contrast , cells overexpressing agap1ggap2/pike - a are smaller and more rounded than control cells .
although the similarity of the gtpase domain in agap1/ggap1 to k - ras , the purified recombinant protein does not bind to gdp , gtp , adp , or atp .
no gtpase activity was detected in full - length agap1 or the isolated gtpase domain .
overexpressed agap1 induced the formation of and was associated with punctate structures containing the endocytic markers transferrin and rab4 35 .
thus , agap1 is a phosphoinositide - dependent arfgap that impacts both the endocytic compartment and actin , consistent with the observations described 27 .
different from the findings on agap1/ggap1 by nie et al , xia and his colleagues demonstrated gtpase domain of agap1/ggap1 and ggap2/pike - a binds to [ p]gtp , but the c - terminal segment of the proteins fail to display gtp - binding .
moreover , they showed the prominent gtpase activity from the full - length agap1/ggap1 and agap2/ggap2/pike - a immunopurified from the cells , transiently transfected with the cdnas encoding the flag - tagged proteins into cos-7 cells .
the turnover number of agap1/ggap1 and agap2/ggap2/pike - a for gtpase activity is similar to gtpase ras ( 0.01 min ) 27 .
furthermore , the authors showed that the c - terminal arfgap domain could regulate the activity of the n - terminal gtpase domain via direct intramolecular interaction .
bacterially purified gtpase domains from agap1/ggap1 and agap2/ggap2/pike - a have very low intrinsic gtpase activity .
addition of the arfgap domain from the same protein ( ggap1 or ggap2 ) significantly increased the gtpase activity 27 .
phosphoinositide lipids bind to ph domain and activate dynamin gtpase activity , which is important in dynamin function during vesicle budding 36 . to test this possibility that phosphatidylinositol lipids also affect pike gtpase activity , we treated pike - s with different phospholipids including phosphatidylinositol 4,5-bisphosphate ( pi-4,5-p2 ) and phosphatidylinositol 3,4,5-trisphosphate ( pi-3,4,5-p3 ) , but failed to detect its activation , presumably because it just contains a partial ph domain .
however , pike - l contains a full module of ph domain and displays high homology with phosphatidylinositol bi- or tri- phosphates .
in fact , our recent data reveal that it selectively binds to pi ( 3,4)p2 , pi ( 3,4,5)p3 and pi ( 3,5)p2 and this interaction mediates pike - l 's gtpase activity ( unpublished data ) .
this observation raises an intriguing and provocative possibility that pike - l might regulates its own gtpase activity through a negative feed - back mechanism using the pi 3-kinase lipid product .
neuronal activity - regulated synaptic -amino-3-hydroxy-5-methylisoxazole-4-propionate receptor ( ampar ) trafficking plays a critical role in synaptic plasticity , a molecular model underlying the learning and memory .
synaptic ampar insertion and removal from postsynaptic membrane mediates n - methyl - d - aspartate receptors ( nmdar ) and mglur i - dependent long - term potentiation ( ltp ) and long - term depression ( ltd ) 37 , 38 . while numerous proteins coupling nmdar to ampar have been demonstrated , little is known the molecular partners that mediate the crosstalk between mglur i and ampar . we have previously shown that protein 4.1n , which binds to the cytoplasmic tail of ampar 39 , interacts with the extreme n - terminus of pike 1 .
moreover , mglur i activation stimulates the formation of homer / pike - l complex , which couples pi 3-kinase to mglur i 5 .
these observations support an intriguing notion that pike - l - homer interaction might couple ampa receptor to mglurs through pike - l association with the postsynaptic proteins 4.1n .
protein 4.1 are a family of multifunctional cytoskeletal components ( 4.1r , 4.1 g , 4.1n and 4.1b ) derived from four related genes , each of which is expressed in the nervous system 40 .
mouse 4.1r knockout supports the notion that protein 4.1 plays an important role in the nervous system , since multiple disturbances in behavior indicate the cerebellar and hippocampal defects , correlating well with the absence of 4.1r in cerebellar granule cells , and hippocampal dentate gyrus cells 41 , 42 .
previous studies indicate that proteins 4.1 exist in both presynaptic and postsynaptic density 39 , 43 , 44 , 45 , 46 .
immunohistochemical studies using a polyclonal 4.1n antibody revealed several patterns of neuronal staining , with localizations in the neuronal cell body , dendrites , and axons . in primary hippocampal cultures ,
mouse 4.1n is enriched at the discrete sites of synaptic contact , colocalizing with the postsynaptic density protein of 95 kda ( a postsynaptic marker ) and glutamate receptor type 1 ( an excitatory postsynaptic marker ) 43 .
previously , 4.1n has been shown to associate with the membrane proximal region of glur1 in vivo and colocalize with ampa receptors at excitatory synapses , where it might implicate in ampa receptors clustering and connecting to the actin cytoskeleton 39 .
conceivably , protein 4.1n may function to confer stability and plasticity to the neuronal membrane via interactions with multiple binding partners , including the spectrin - actin - based cytoskeleton , integral membrane channels and receptors , and postsynaptic protein like pike - l .
this finding conforms to our current model in postsynaptic glutamate receptors clustering and synaptogenesis mediated by homer - shank interaction by docking mglurs to the nmdars .
pike - s gtpase is activated by plc-1 , which acts as a physiologic guanine nucleotide exchange factor ( gef ) for pike .
the identification of pike - l and -a isoforms , which contain an arfgap domain , might shed light on the molecular mechanism how pike gtpase is negatively regulated .
the arfgap domain possesses potent gap activity on arf gtpase and its internal gtpase domain .
moreover , this gap activity is mediated by phosphoinositol lipids through ph domain of pike , suggesting a negative feed - back mechanism between pike / pi 3-kinase singaling .
besides its anti - apoptotic role in mglur i cascade , pike - l might also implicate in synaptic plasticity by coupling mglur i to amap receptor .
pike - a may have even broader relevance resulting from its subcellular localization ( in both the nucleus and the cytoplasm ) and tissue distribution .
pike - a might contribute to cancer progression by promoting cancer cell invasion and survival through up - regulating akt .
diagram of three pike isoforms.pike-l , an alternatively spliced form of pike , which is several hundred amino acids longer than the original form of pike , designated as pike - s ( bankit475414 ( ay128689 , human ) ) .
in addition to the gtpase and ph domains shared by pike - s and pike - l , pike - l contains an arfgap domain and two ankyrin repeats .
pike - a contains the gtpase , ph , arfgap and ankyrin repeats domains present in pike - l but lacks the proline - rich domains ( prd ) containing n - terminus , which protein 4.1n , pi 3-kinase and plc-1 bind to .
plc-1/pike - s / nuclear pi 3-kinase signalling : ngf treatment of pc12 cells provokes plc-1 nuclear translocation , and stimulates pike - s gtpase to bind gtp .
ngf also causes 4.1n to translocate to the nucleus over a period of hours , lagging behind the translocation of pi 3-kinase and the peak activation of pike elicited by ngf .
the decline of activated nuclear pi 3-kinase , which coincides with the appearance of nuclear 4.1n , might involve 4.1n sequestering pike away from nuclear pi 3-kinase .
the decline of pike 's ngf - induced gtpase activation takes place at about the same time and so also may participate in the decline of nuclear pi 3-kinase .
pike binding proteins : protein 4.1n and pi 3-kinase share the same binding motif on the n - terminus of pike .
mglur i adaptor protein homer 1 interacts with pike through  homer binding motif pxpf ( a.a .
akt associates with pike - a through its gtpase and c - terminal ankyrin repeats domains .
 pike ( pi 3-kinase enhancer ) is a recently identified brain specific nuclear gtpase , which binds pi 3-kinase and stimulates its lipid kinase activity . 
 nerve growth factor treatment leads to pike activation by triggering the nuclear translocation of phospholipase c-1 ( plc-1 ) , which acts as a physiologic guanine nucleotide exchange factor ( gef ) for pike through its sh3 domain . to date , three forms of pike have been characterized : pike - s , pike - l and pike - a . 
 pike - s is initially identified shorter isoform . 
 pike - l , a longer isoform of pike gene , differs from pike - s by c - terminal extension containing arf - gap ( adp ribosylation factor - gtpase activating protein ) and two ankyrin repeats domains . 
 in contrast to the exclusive nuclear localization of pike - s , pike - l occurs in both the nucleus and the cytoplasm . 
 pike - l physiologically associates with homer 1 , an mglur i binding adaptor protein . 
 the homer / pike - l complex couples pi 3-kinase to mglur i and regulates a major action of group i mglurs , prevention of neuronal apoptosis . 
 more recently , a third pike isoform , pike - a was identified in human glioblastoma multiforme brain cancers . unlike the brain specific pike - l and -s isoforms , pike - a distributes in various tissues . 
 pike - a contains the same domains present in pike - l but lacks n - terminal proline - rich domain ( prd ) , which binds pi 3-kinase and plc-1 . 
 instead , pike - a specifically binds to active akt and upregulates its activity in a gtp - dependent manner , mediating human cancer cell invasion and preventing apoptosis . 
 thus , pike extends its roles from the nucleus to the cytoplasm , mediating cellular processes from cell invasion to programmed cell death . 