Neurofibromatosis type 1 (NF1), a genetic disease that affects 1 in 3,000, is 
caused by loss of a large evolutionary conserved protein that serves as a GTPase 
Activating Protein (GAP) for Ras. Among Drosophila melanogaster Nf1 (dNf1) null 
mutant phenotypes, learning/memory deficits and reduced overall growth resemble 
human NF1 symptoms. These and other dNf1 defects are relatively insensitive to 
manipulations that reduce Ras signaling strength but are suppressed by 
increasing signaling through the 3'-5' cyclic adenosine monophosphate (cAMP) 
dependent Protein Kinase A (PKA) pathway, or phenocopied by inhibiting this 
pathway. However, whether dNf1 affects cAMP/PKA signaling directly or indirectly 
remains controversial. To shed light on this issue we screened 486 1(st) and 
2(nd) chromosome deficiencies that uncover >80% of annotated genes for dominant 
modifiers of the dNf1 pupal size defect, identifying responsible genes in 
crosses with mutant alleles or by tissue-specific RNA interference (RNAi) 
knockdown. Validating the screen, identified suppressors include the previously 
implicated dAlk tyrosine kinase, its activating ligand jelly belly (jeb), two 
other genes involved in Ras/ERK signal transduction and several involved in 
cAMP/PKA signaling. Novel modifiers that implicate synaptic defects in the dNf1 
growth deficiency include the intersectin-related synaptic scaffold protein 
Dap160 and the cholecystokinin receptor-related CCKLR-17D1 drosulfakinin 
receptor. Providing mechanistic clues, we show that dAlk, jeb and CCKLR-17D1 are 
among mutants that also suppress a recently identified dNf1 neuromuscular 
junction (NMJ) overgrowth phenotype and that manipulations that increase 
cAMP/PKA signaling in adipokinetic hormone (AKH)-producing cells at the base of 
the neuroendocrine ring gland restore the dNf1 growth deficiency. Finally, 
supporting our previous contention that ALK might be a therapeutic target in 
NF1, we report that human ALK is expressed in cells that give rise to NF1 tumors 
and that NF1 regulated ALK/RAS/ERK signaling appears conserved in man.