In cellular biology, paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse over a relatively short distance (local action), as opposed to cell signaling by endocrine factors, hormones which travel considerably longer distances via the circulatory system; juxtacrine interactions; and autocrine signaling. Cells that produce paracrine factors secrete them into the immediate extracellular environment. Factors then travel to nearby cells in which the gradient of factor received determines the outcome. However, the exact distance that paracrine factors can travel is not certain.
Although paracrine signaling elicits a diverse array of responses in the induced cells, most paracrine factors utilize a relatively streamlined set of receptors and pathways. In fact, different organs in the body - even between different species - are known to utilize similar sets of paracrine factors in differential development. The highly conserved receptors and pathways can be organized into four major families based on similar structures: fibroblast growth factor (FGF) family, Hedgehog family, Wnt family, and TGF-β superfamily. Binding of a paracrine factor to its respective receptor initiates signal transduction cascades, eliciting different responses.
Paracrine factors induce competent responders In order for paracrine factors to successfully induce a response in the receiving cell, that cell must have the appropriate receptors available on the cell membrane to receive the signals, also known as being competent. Additionally, the responding cell must also have the ability to be mechanistically induced.
Fibroblast growth factor (FGF) family Although the FGF family of paracrine factors has a broad range of functions, major findings support the idea that they primarily stimulate proliferation and differentiation. To fulfill many diverse functions, FGFs can be alternatively spliced or even have different initiation codons to create hundreds of different FGF isoforms. One of the most important functions of the FGF receptors (FGFR) is in limb development. This signaling involves nine different alternatively spliced isoforms of the receptor. Fgf8 and Fgf10 are two of the critical players in limb development. In the forelimb initiation and limb growth in mice, axial (lengthwise) cues from the intermediate mesoderm produces Tbx5, which subsequently signals to the same mesoderm to produce Fgf10. Fgf10 then signals to the ectoderm to begin production of Fgf8, which also stimulates the production of Fgf10. Deletion of Fgf10 results in limbless mice. Additionally, paracrine signaling of Fgf is essential in the developing eye of chicks. The fgf8 mRNA becomes localized in what differentiates into the neural retina of the optic cup. These cells are in contact with the outer ectoderm cells, which will eventually become the lens. Phenotype and survival of mice after knockout of some FGFR genes:
Receptor tyrosine kinase (RTK) pathway Paracrine signaling through fibroblast growth factors and its respective receptors utilizes the receptor tyrosine pathway. This signaling pathway has been highly studied, using Drosophila eyes and human cancers. Binding of FGF to FGFR phosphorylates the idle kinase and activates the RTK pathway. This pathway begins at the cell membrane surface, where a ligand binds to its specific receptor. Ligands that bind to RTKs include fibroblast growth factors, epidermal growth factors, platelet-derived growth factors, and stem cell factor. This dimerizes the transmembrane receptor to another RTK receptor, which causes the autophosphorylation and subsequent conformational change of the homodimerized receptor. This conformational change activates the dormant kinase of each RTK on the tyrosine residue. Due to the fact that the receptor spans across the membrane from the extracellular environment, through the lipid bilayer, and into the cytoplasm, the binding of the receptor to the ligand also causes the trans phosphorylation of the cytoplasmic domain of the receptor. An adaptor protein (such as SOS) recognizes the phosphorylated tyrosine on the receptor. This protein functions as a bridge which connects the RTK to an intermediate protein (such as GNRP), starting the intracellular signaling cascade. In turn, the intermediate protein stimulates GDP-bound Ras to the activated GTP-bound Ras. GAP eventually returns Ras to its inactive state. Activation of Ras has the potential to initiate three signaling pathways downstream of Ras: Ras→Raf→MAP kinase pathway, PI3 kinase pathway, and Ral pathway. Each pathway leads to the activation of transcription factors which enter the nucleus to alter gene expression.
RTK receptor and cancer Paracrine signaling of growth factors between nearby cells has been shown to exacerbate carcinogenesis. In fact, mutant forms of a single RTK may play a causal role in very different types of cancer. The Kit proto-oncogene encodes a tyrosine kinase receptor whose ligand is a paracrine protein called stem cell factor (SCF), which is important in hematopoiesis (formation of cells in blood). The Kit receptor and related tyrosine kinase receptors actually are inhibitory and effectively suppresses receptor firing. Mutant forms of the Kit receptor, which fire constitutively in a ligand-independent fashion, are found in a diverse array of cancerous malignancies.
RTK pathway and cancer Research on thyroid cancer has elucidated the theory that paracrine signaling may aid in creating tumor microenvironments. Chemokine transcription is upregulated when Ras is in the GTP-bound state. The chemokines are then released from the cell, free to bind to another nearby cell. Paracrine signaling between neighboring cells creates this positive feedback loop. Thus, the constitutive transcription of upregulated proteins form ideal environments for tumors to arise. Effectively, multiple bindings of ligands to the RTK receptors overstimulates the Ras-Raf-MAPK pathway, which overexpresses the mitogenic and invasive capacity of cells.
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