BIOLOGICAL OVERVIEW

A brief detour through one group of mammalian receptors will serve to introduce and clarify the Drosophila gene hopscotch. Mammalian cytokines, lymphokines and growth factors interact with the cytokine receptor superfamily. Despite a lack of catalytic kinase domains, these receptors combine ligand binding with the induction of tyrosine phosphorylation. This means that members of the Janus kinase (JAK) family of cytoplasmic protein tyrosine kinases physically associate with ligand-bound receptors. It is this association that results in tyrosine phosphorylation and activation.

Activated JAKs phosphorylate the receptors as well as cytoplasmic proteins belonging to a family of transcription factors called signal transducers and activators of transcription (STATs). This JAK-STAT pathway is shared by all members of the cytokine receptor superfamily. hopscotch has been identified as the Drosophila JAK homolog. marelle, or DSTAT has been identified as the fly's STAT homolog (Ihle, 1994).

The JAK-STAT pathway regulates the expression of pair rule gene even skipped early in embryogenesis. Cooperativity in a number of positive regulator mechanisms might be required to provide an appropriate level of expression of eve in certain stripes. If the function of the JAK-STAT pathway were simply to upregulate the expression of eve in specific stripes, then the level of activation provided by the HOP-STAT system will depend on the number of STAT-binding sites present in the stripe-specific enhancer regions of eve. This might hold for activation of other pair rule genes as well. If the mechanism of activation of the JAK-STAT pathway is conserved between mammals and Drosophila, then HOP should be activated by its interaction with a membrane-bound receptor lacking a kinase domain. Because Hunchback and Knirps set the anterior and posterior borders of eve stripe 3, the JAK-STAT pathwy is not needed to spatially activate eve. It is not known which, if any, receptor is required for activation of the JAK-STAT pathway early in embryogenesis, but it is clear that the pathway is established maternally (Hou, 1997).

hopscotch has been identified as one of more than 50 Drosophila oncogenes, that is, genes that cause tumors. Tumorous-lethal (Tum-l), a hopscotch mutation, causes formation of melanotic tumors and proliferative defects in larval blood cells. Tum-l is an X-linked dominant mutation that causes melanotic tumor formation and temperature sensitive lethality. The larval tissues that produce blood cells are the lymph glands, a group of small organs arranged in lobed pairs on either side of the heart (the dorsal vessel). Undifferentiated stem cells produce two classes of mature blood cells. The first class is composed of podocytes and lamellocytes, macrophage-like cells involved in encapsulation and phagocytosis of foreign objects. The second class comprise crystal cells, involved in melanization. Tum-l causes hypertrophy (enlargement) of larval lymph glands and premature differentiation of lamellocytes.

HOP can cause neoplasia (literally "new growth;" figuratively, tumors) through one of two distinct mechanisms. The first is mutational. The original hop mutation is a single nucleotide amino acid substitution in the hop gene. The second mechanism is overexpression. Overproduction of wild type HOP by fusion of the gene to a heat shock promoter and expression during the second or third instar period also results in tumor formation. Overexpression of D-raf results in a similar phenotype to overexpression of hop. Is there a link between the two? Vertebrate epidermal growth factor signaling induces the activation of JAK1. It is tempting to speculate that DER/Torpedo/EGF-R signaling, known to transduce through the ras/raf pathway, may activate HOP as well (Harrison, 1995).

GENE STRUCTURE

Bases in 5' UTR -620

Exons - ten

Bases in 3' UTR - 1064

PROTEIN STRUCTURE

Amino Acids - 1177

Structural Domains

HOP has homology at its carboxyl terminus to the catalytic domain of tyrosine kinases. There is a short nuclear localization signal (amino acids 315-320) (Binari, 1994.)

date revised: 23 December 97

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