Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex.
Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder associated with mutations in TSC1, which codes for hamartin, or TSC2, which codes for tuberin. The brain is one of the most severely affected organs, and CNS lesions include cortical tubers and subependymal giant cell astrocytomas, resulting in mental retardation and seizures. Tuberin and hamartin function together as a complex in mammals and Drosophila. We report here the association of Pam, a protein identified as an interactor of Myc, with the tuberin-hamartin complex in the brain. The C terminus of Pam containing the RING zinc finger motif binds to tuberin. Pam is expressed in embryonic and adult brain as well as in cultured neurons. Pam has two forms in the rat CNS, an approximately 450-kDa form expressed in early embryonic stages and an approximately 350-kDa form observed in the postnatal period. In cortical neurons, Pam co-localizes with tuberin and hamartin in neurites and growth cones. Although Pam function(s) are yet to be defined, the highly conserved Pam homologs, HIW (Drosophila) and RPM-1 (Caenorhabditis elegans), are neuron-specific proteins that regulate synaptic growth. Here we show that HIW can genetically interact with the Tsc1.Tsc2 complex in Drosophila and could negatively regulate Tsc1.Tsc2 activity. Based on genetic studies, HIW has been implicated in ubiquitination, possibly functioning as an E3 ubiquitin ligase through the RING zinc finger domain. Therefore, we hypothesize that Pam, through its interaction with tuberin, could regulate the ubiquitination and proteasomal degradation of the tuberin-hamartin complex particularly in the CNS.
Murthy
Vanishree
V
Molecular Neurogenetics Unit, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Han
Sangyeul
S
Beauchamp
Roberta L
RL
Smith
Nicole
N
Haddad
Luciana A
LA
Ito
Naoto
N
Ramesh
Vijaya
V
D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism* / Q000502:physiology; D002460:Cell Line; D002490:Central Nervous System / Q000378:metabolism; D017124:Conserved Sequence; D018076:DNA, Complementary / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins; D005838:Genotype; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D006899:Mixed Function Oxygenases; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010641:Phenotype; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D014162:Transfection; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D016335:Zinc Fingers
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; D029721:Drosophila Proteins; C409633:HIW protein, Drosophila; D009419:Nerve Tissue Proteins; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C000624650:TSC1 protein, human; C000624653:TSC2 protein, human; C000624652:Tsc1 protein, rat; C000624655:Tsc2 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D006899:Mixed Function Oxygenases; C114022:MYCBP2 protein, human; D044767:Ubiquitin-Protein Ligases; D005982:Glutathione Transferase