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Macrophages are an ancient blood cell lineage critical for homeostasis and defence against pathogens. Although their numbers were long thought to be sustained solely by haematopoietic organs, it has recently become clear that their proliferation, or self‐renewal, also plays a major role. In the Drosophila larva, macrophages undergo a phase of rapid self‐renewal, making this an attractive model for elucidating the signals and regulatory mechanisms involved. However, a central self‐renewal pathway has not been identified in this system. Here, we show that the PDGF‐ and VEGF‐receptor related (Pvr) pathway fulfils this role. Our data show that two of the three known Pvr ligands, PDGF‐ and VEGF‐related factor 2 (Pvf2) and Pvf3, are major determinants of overall macrophage numbers, yet they each act in a temporally independent manner and via distinct mechanisms. While Pvf3 is needed prior to the self‐renewal period, we find that Pvf2 is critical specifically for expanding the larval macrophage population. We further show that Pvf2 is a potent macrophage mitogen that is kept at limiting quantities by its transient expression in a remarkably small number of blood cells. Together, these data support a novel mechanism for the regulation of macrophage self‐renewal rates by the dynamic transcriptional control of Pvf2. Given the strong parallels that exist between Drosophila and vertebrate macrophage systems, it is likely that a similar self‐renewal control mechanism is at play across animal phyla. [ABSTRACT FROM AUTHOR]

Tyrosine phosphorylation-dependent signalling is coordinated by the opposing actions of protein tyrosine kinases ( PTKs) and protein tyrosine phosphatases ( PTPs). There is a growing list of adaptor proteins that interact with PTPs and facilitate the dephosphorylation of substrates. The extent to which any given adaptor confers selectivity for any given substrate in vivo remains unclear. Here we have taken advantage of Drosophila melanogaster as a model organism to explore the influence of the SH3/ SH2 adaptor protein Dock on the abilities of the membrane ( PTP61Fm)- and nuclear ( PTP61Fn)-targeted variants of PTP61F (the Drosophila othologue of the mammalian enzymes PTP1B and TCPTP respectively) to repress PTK signalling pathways in vivo. PTP61Fn effectively repressed the eye overgrowth associated with activation of the epidermal growth factor receptor ( EGFR), PTK, or the expression of the platelet-derived growth factor/vascular endothelial growth factor receptor ( PVR) or insulin receptor (InR) PTKs. PTP61Fn repressed EGFR and PVR-induced mitogen-activated protein kinase signalling and attenuated PVR-induced STAT92E signalling. By contrast, PTP61Fm effectively repressed EGFR- and PVR-, but not InR-induced tissue overgrowth. Importantly, coexpression of Dock with PTP61F allowed for the efficient repression of the InR-induced eye overgrowth, but did not enhance the PTP61Fm-mediated inhibition of EGFR and PVR-induced signalling. Instead, Dock expression increased, and PTP61Fm coexpression further exacerbated the PVR-induced eye overgrowth. These results demonstrate that Dock selectively enhances the PTP61Fm-mediated attenuation of InR signalling and underscores the specificity of PTPs and the importance of adaptor proteins in regulating PTP function in vivo. [ABSTRACT FROM AUTHOR]