你认为你的细胞只是简单的积木，无意识的和静态的，就像墙上的砖块?如果是的话，再想想!细胞能够探测到周围发生的事情，并且能够对来自邻居和环境的提示做出实时反应。此时此刻，你的细胞正在以化学信号分子的形式发送和接收数以百万计的信息!
在本文中，我们将研究细胞之间如何通信的基本原理。我们将首先了解细胞-细胞信号是如何工作的，然后考虑在我们体内发生的不同种类的短距离和长程信号。
Overview of cell signaling
细胞通常使用化学信号进行交流。这些化学信号是由发送细胞产生的蛋白质或其他分子，通常由细胞分泌并释放到细胞外空间。在那里，它们可以像漂流瓶一样漂浮到邻近的细胞。
并不是所有的细胞都能“听到”特定的化学信息。为了检测到一个信号(也就是说，成为一个目标细胞，target cell)，相邻的细胞必须有合适的受体（receptor ）来接收这个信号。当信号分子与受体结合时，它改变了受体的形状或活动，触发了细胞内部的变化。信号分子通常被称为配体（ligands），配体是专门与其他分子(如受体)结合的分子的总称。
所以一个细胞在不同的配受体语境下，可能是受体也可能是配体。
配体所携带的信息通常通过细胞内的化学信使链传递。最终，它会唤起细胞的变化，如基因活性的改变，甚至诱导一个完整的过程，如细胞分裂。因此，原始的细胞间(细胞间)信号被转化为触发反应的细胞内(细胞内)信号。
你可以在有关配体和受体、信号传递和细胞反应的文章中了解更多这是如何工作的。
Ligands & receptors
就像千里之行始于足下一样，细胞内部复杂的信号通路也始于一个关键事件——信号分子或配体（Ligands ）与接收分子或受体（receptors ）结合。
受体和配体有很多种形式，但它们都有一个共同点:它们都是紧密匹配的配对，一个受体只能识别一个(或几个)特定的配体，一个配体只能与一个(或几个)目标受体结合。配体与受体结合会改变受体的形状或活性，使其能够传递信号或直接在细胞内部产生变化
在这一节中，我们将研究不同类型的受体和配体，看看它们是如何相互作用，将细胞外的信息转化为细胞内的变化。
受体有很多种，但可分为两类:细胞内受体，即存在于细胞内部(细胞质或细胞核中);细胞表面受体，即存在于质膜中。
胞内受体
细胞内受体是在细胞内部发现的受体蛋白，通常在细胞质或细胞核中。在大多数情况下，细胞内受体的配体是小的疏水(憎水)分子，因为它们必须能够穿过质膜才能到达受体。例如，疏水类固醇激素，如性激素雌二醇(雌激素)和睾酮的主要受体是细胞内的。
当一种激素进入细胞并与受体结合时，它会导致受体改变形状，从而使受体-激素复合物进入细胞核(如果已经不存在的话)并调节基因活性。激素结合暴露了受体中具有DNA结合活性的区域，这意味着它们可以附着在特定的DNA序列上。这些序列被发现在细胞DNA的某些基因旁边，当受体与这些基因结合时，它改变了它们的转录水平。
许多信号通路，包括细胞内和细胞表面受体，导致基因转录的变化。然而，细胞内受体是独特的，因为它们非常直接地引起这些变化，与DNA结合并改变转录本身。
细胞表面受体
细胞表面受体是与细胞外表面配体结合的膜锚定蛋白。在这种类型的信号传导中，配体不需要穿过质膜。因此，许多不同种类的分子(包括大分子、亲水分子或“亲水”分子)可以作为配体。
一个典型的细胞表面受体有三个不同的区域，即蛋白质区域:一个细胞外(“细胞外”)配体结合区域，一个延伸细胞膜的疏水区域，以及一个通常传递信号的细胞内(“细胞内”)区域。这些区域的大小和结构取决于受体的类型，疏水区域可能由交叉在细胞膜上的多个氨基酸延伸组成。
细胞表面受体有很多种，但在这里我们将看到三种常见的类型:配体门控离子通道，G蛋白偶联受体，受体酪氨酸激酶。
配体门控离子通道
配体门控离子通道是指随着配体的结合而打开的离子通道。为了形成通道，这种类型的细胞表面受体有一个跨膜区域，中间有一个亲水(亲水)通道。该通道允许离子通过膜而不必接触磷脂双分子层的疏水性核心。
当一个配体结合到细胞外区域的通道,蛋白质的结构发生变化,这样一个特定类型的离子,如 Ca2+或Cl−可以通过。在某些情况下，事实正好相反：通道通常是打开的，配体结合使其关闭。细胞内离子水平的变化可以改变其他分子的活性，如离子结合酶和电压敏感通道，以产生反应。神经元或神经细胞有配体门控通道，这些通道被神经递质结合。
G蛋白偶联受体
蛋白偶联受体(GPCRs)是一个庞大的细胞表面受体家族，具有共同的结构和信号传导方式。GPCR家族的成员都有七个不同的蛋白质片段穿过细胞膜，它们通过一种叫做G蛋白的蛋白质在细胞内传递信号。
受体酪氨酸激酶
酶联受体是一种细胞表面受体，具有与酶相关的胞内结构域。在某些情况下，受体的细胞内区域实际上是一种可以催化反应的酶。其他酶联受体有一个与酶5^5相互作用的胞内结构域。
受体酪氨酸激酶(RTKs)是一类在人类和许多其他物种中发现的酶联受体。激酶只是一种酶的名称，它把磷酸基转移到蛋白质或其他目标上，而受体酪氨酸激酶专门把磷酸基转移到氨基酸酪氨酸上。
配体的类型
配体由信号细胞产生，并与靶细胞内或靶细胞上的受体相互作用，有许多不同的种类。有些是蛋白质，有些是疏水分子，比如类固醇，还有一些是气体，比如一氧化氮。在这里，我们将看一些不同类型的配体的例子。我们熟悉的类固醇激素包括女性性激素雌二醇(雌激素的一种)和男性性激素睾酮。维生素D是在皮肤中利用光的能量合成的一种分子，它是类固醇激素的另一个例子。因为它们是疏水性的，这些激素在穿过细胞膜时没有困难，但它们必须与载体蛋白质结合才能通过(水)血液。
结合在细胞外部的配体
水溶性配体是极性的或带电荷的，不能轻易穿过质膜。因此，大多数水溶性配体结合到细胞表面受体的细胞外区域，停留在细胞的外表面。肽(蛋白质)配体是水溶性配体中数量最多、种类最多的一类。例如，生长因子、胰岛素等激素和某些神经递质都属于这一类。肽配体的长度可以从几个氨基酸(如镇痛脑啡肽)到上百个或更多的氨基酸。
能进入细胞的配体
小的疏水配体可以通过质膜并与细胞核或细胞质中的细胞内受体结合。在人体中，这类最重要的配体是类固醇激素。
信号传递途径
当一个细胞的信号分子(配体)与另一个细胞的受体结合，信号传递过程完成了吗?
如果我们说的是细胞内受体，它们在细胞内结合配体并直接激活基因，答案可能是肯定的。然而，在大多数情况下，答案是否定的——绝不可能!对于位于细胞膜上的受体来说，信号必须通过细胞中的其他分子传递，就像一种“电话”的细胞游戏。
在细胞内传递信号的分子链被称为细胞内信号转导途径。在这里，我们将看到细胞内信号转导途径的一般特征，以及在这些途径中常用的一些中继机制。
Binding initiates a signaling pathway
当配体与细胞表面受体结合时，受体的细胞内结构域(细胞内的一部分)会以某种方式改变。通常，它会呈现出一种新的形状，这可能使它具有酶的活性，或者使它与其他分子结合。
受体的变化引发了一系列的信号传递事件。例如，受体可能打开细胞内的另一个信号分子，反过来激活它自己的目标。这种连锁反应最终会导致细胞行为或特性的改变，如下图所示。
由于信息的流向是有方向性的，上游（upstream ）这个术语通常用来描述在接力链中较早出现的分子和事件，而下游（upstream ）则可以用来描述那些较晚出现的分子和事件(相对于特定的感兴趣的分子)。例如，在图中，受体在配体的下游但在细胞质蛋白质的上游。许多信号转导途径将初始信号放大，使得一个配体分子可以导致下游靶点的多个分子的激活。
传递信号的分子通常是蛋白质。然而，离子和磷脂等非蛋白分子也可以发挥重要作用。
上面的卡通特征是一堆标记为“开”或“关”的斑点(信号分子)。“一个斑点的开或关到底是什么意思?”活化或灭活蛋白质的方法多种多样。然而，改变蛋白质活性最常见的方法之一是在蛋白质的一个或多个位点上添加一个磷酸基，这个过程称为磷酸化。
磷酸化通常起到开关的作用，但其作用在不同的蛋白质中有所不同。有时，磷酸化会使蛋白质更活跃(例如，增加催化作用或使其与伙伴结合)。在其他情况下，磷酸化可能使蛋白质失活或导致其分解。
一般来说，磷酸化不是永久的。为了将蛋白质翻转回非磷酸化状态，细胞中有一种被称为磷酸酶的酶，它可以将一个磷酸基从它们的目标上移除。
凡请背诵以下名词解释,并注意各个通路之间的关系。
巨噬细胞游走抑制因子：
macrophage migration inhibitory factor (MIF)
A Novel MIF Signaling Pathway Drives the Malignant Character of Pancreatic Cancer by Targeting NR3C2
Pancreatic cancers with aberrant expression of macrophage migration inhibitory factor (MIF) are particularly aggressive. To identify key signaling pathways that drive disease aggressiveness in tumors with high MIF expression, we analyzed the expression of coding and noncoding genes in high and low MIF-expressing tumors in multiple cohorts of pancreatic ductal adenocarcinoma (PDAC) patients.
转化生长因子
Transforming growth factor-β (TGF-β)
https://www.cellsignal.com/contents/science-cst-pathways-developmental-biology/tgf-signaling/pathways-tgfb
Transforming growth factor-β (TGF-β) superfamily signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. In general, signaling is initiated with ligand-induced oligomerization of serine/threonine receptor kinases and phosphorylation of the cytoplasmic signaling molecules Smad2 and Smad3 for the TGF-β/activin pathway, or Smad1/5/9 for the bone morphogenetic protein (BMP) pathway.
B和t淋巴细胞衰减器(BTLA)
B- and T-lymphocyte attenuator (BTLA)
BTLA/HVEM Signaling: Milestones in Research and Role in Chronic Hepatitis B Virus Infection
B- and T-lymphocyte attenuator (BTLA) is an immune-regulatory receptor, similar to CTLA-4 and PD-1, and is mainly expressed on B-, T-, and all mature lymphocyte cells. Herpes virus entry mediator (HVEM)-BTLA plays a critical role in immune tolerance and immune responses which are areas of intense research. However, the mechanisms of the BTLA and the BTLA/HVEM signaling pathway in human diseases remain unclear. This review describes the research milestones of BTLA and HVEM in chronological order and their role in chronic HBV infection.
骨形态发生蛋白(BMP)
Bone Morphogenetic Protein (BMP)
Bone Morphogenetic Protein (BMP) signaling in development and human diseases
Bone Morphogenetic Proteins (BMPs) are a group of signaling molecules that belongs to the Transforming Growth Factor-β (TGF-β) superfamily of proteins. Initially discovered for their ability to induce bone formation, BMPs are now known to play crucial roles in all organ systems. BMPs are important in embryogenesis and development, and also in maintenance of adult tissue homeostasis.
激活素
Activin signaling
Activin signaling as an emerging target for therapeutic interventions
After the initial discovery of activins as important regulators of reproduction, novel and diverse roles have been unraveled for them. Activins are expressed in various tissues and have a broad range of activities including the regulation of gonadal function, hormonal homeostasis, growth and differentiation of musculoskeletal tissues, regulation of growth and metastasis of cancer cells, proliferation and differentiation of embryonic stem cells, and even higher brain functions. Activins signal through a combination of type I and II transmembrane serine/threonine kinase receptors. Activin receptors are shared by multiple transforming growth factor-β (TGF-β) ligands such as myostatin, growth and differentiation factor-11 and nodal.
神经调节蛋白
Neuregulin 1 (NRG-1)
The Importance of the NRG-1/ErbB4 Pathway for Synaptic Plasticity and Behaviors Associated with Psychiatric Disorders
Neuregulin 1 (NRG-1) and its receptor ErbB4 have emerged as biologically plausible schizophrenia risk factors, modulators of GABAergic and dopaminergic neurotransmission, and as potent regulators of glutamatergic synaptic plasticity. NRG-1 acutely depotentiates LTP in hippocampal slices, and blocking ErbB kinase activity inhibits LTP reversal by theta-pulse stimuli (TPS), an activity-dependent reversal paradigm. NRG-1/ErbB4 signaling in parvalbumin (PV) interneurons has been implicated in inhibitory transmission onto pyramidal neurons.
纤维母细胞生长因子
Fibroblast Growth Factor(FGFs)
Emerging roles of FGF signaling in hepatocellular carcinoma
FGF was identified forty years ago and has been extensionally studied over the last three decades (23). There are 22 human FGFs, which are encoded by different genes. It has been known that most FGFs are secreted and contain signal-peptide sequences (23). Structurally, the FGF protein has FGFR-binding domains and HS (heparin sulfate)-binding domains, which is required for FGFR dimerization and activation
血小板源性生长因子
Platelet-derived Growth Factor (PDGF) Signaling Pathway
https://www.sinobiological.com/resource/cytokines/pdgf-signaling-pathway
Platelet-derived growth factor (PDGF) signaling network consists of four ligands, PDGFA-D, and two receptors, PDGFRalpha and PDGFRbeta. All PDGFs function as secreted, disulphide-linked homodimers, but only PDGFA and B can form functional heterodimers.
血管内皮生长因子
vascular endothelial growth factor，VEGF
https://www.tocris.com/cn/pathways/vegf-signaling-pathway
The VEGF (vascular endothelial growth factor) signaling pathway regulates vascular development in the embryo (vasculogenesis) and new blood vessel formation (angiogenesis). The VEGFR can induce several cellular processes which are common to many growth factor receptors, including cell migration, proliferation and survival.
胰岛素生长因子
Insulin-Like Growth Factor (IGF)
Insulin-Like Growth Factor (IGF) Pathway Targeting in Cancer: Role of the IGF Axis and Opportunities for Future Combination Studies
Despite a strong preclinical rationale for targeting the insulin-like growth factor (IGF) axis in cancer, clinical studies of IGF-1 receptor (IGF-1R)-targeted monotherapies have been largely disappointing, and any potential success has been limited by the lack of validated predictive biomarkers for patient enrichment. A large body of preclinical evidence suggests that the key role of the IGF axis in cancer is in driving treatment resistance, via general proliferative/survival mechanisms, interactions with other mitogenic signaling networks, and class-specific mechanisms such as DNA damage repair.
肿瘤坏死因子
Tumor necrosis factor (TNF)
https://www.creative-diagnostics.com/tnf-a-signaling-pathway.htm
Tumor necrosis factor (TNF) is a kind of cytokine with many biological effects. It promotes cell growth, differentiation, apoptosis and inflammation by binding to specific receptors on the cell membrane. TNF-α belongs to the TNF family and can activate ERK (extracellular signal 2 regulated protein kinase), Caspase protease, and JNK. It also has independent pathways to achieve its biological functions such as cytotoxicity, antiviral, immune regulation and apoptosis. Since TNF-α is directly related to cell homeostasis and many human diseases, such as tumors, research on TNF-α signaling pathway has become a hot topic in biomedical research in the past decade.
白血病抑制因子受体
leukemia inhibitory factor receptor
https://ghr.nlm.nih.gov/gene/LIFR#:~:text=LIFR%20acts%20as%20a%20receptor%20for%20a%20molecule,growth%20and%20division%20%28proliferation%29%2C%20maturation%20%28differentiation%29%2C%20and%20survival.
The LIFR gene provides instructions for making the leukemia inhibitory factor receptor (LIFR) protein. This receptor spans the cell membrane, which allows it to attach (bind) to other proteins, called ligands, outside the cell and send signals inside the cell that help the cell respond to its environment. Ligands and receptors fit together like keys into locks.
集落刺激因子
colony-stimulating factor-1 (CSF-1)
CSF-1 Receptor Signaling in Myeloid Cells
The CSF-1 receptor (CSF-1R) is activated by the homodimeric growth factors colony-stimulating factor-1 (CSF-1) and interleukin-34 (IL-34). It plays important roles in development and in innate immunity by regulating the development of most tissue macrophages and osteoclasts, of Langerhans cells of the skin, of Paneth cells of the small intestine, and of brain microglia. It also regulates the differentiation of neural progenitor cells and controls functions of oocytes and trophoblastic cells in the female reproductive tract.
促）红细胞生成素
erythropoietin (EPO)
Erythropoietin Pathway: A Potential Target for the Treatment of Depression
Emerging EPO and EPO receptor regulators and signal transducers
As essential mediators of red cell production, erythropoietin (EPO) and its cell surface receptor (EPO receptor [EPOR]) have been intensely studied. Early investigations defined basic mechanisms for hypoxia-inducible factor induction of EPO expression, and within erythroid progenitors EPOR engagement of canonical Janus kinase 2/signal transducer and activator of transcription 5 (JAK2/STAT5), rat sarcoma/mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS/MEK/ERK), and phosphatidylinositol 3-kinase (PI3K) pathways.
钠尿肽受体2 (NPR2)
Natriuretic peptide receptor 2 (NPR2)
Natriuretic peptide receptor 2 (NPR2) localized in bovine oocyte underlies a unique mechanism for C-type natriuretic peptide (CNP)-induced meiotic arrest
Meiosis is of prime importance for successful gametogenesis, and insufficient maintenance of oocyte meiotic arrest compromises oocyte developmental competence. Recent studies have demonstrated that the C-type natriuretic peptide (CNP)-Natriuretic peptide receptor 2 (NPR2) pathway can inhibit mammalian oocyte meiotic resumption. In mouse and porcine, the inhibitory effect of mural granulosa cell (MGC)-derived CNP on oocyte meiotic resumption is mediated by NPR2 localized in cumulus cells (CCs) surrounding the oocytes. However, in the present study, we identified a novel mechanism for CNP-induced meiotic arrest that appears to be unique to bovine oocytes.
蛋白酶激活受体
Proteinase-activated receptors (PARs)
Proteinase-activated receptors (PARs) – focus on receptor-receptor-interactions and their physiological and pathophysiological impact
Proteinase-activated receptors (PARs) are a subfamily of G protein-coupled receptors (GPCRs) with four members, PAR1, PAR2, PAR3 and PAR4, playing critical functions in hemostasis, thrombosis, embryonic development, wound healing, inflammation and cancer progression.
细胞外基质
extracellular matrix (ECM) receptors
ECM receptors in neuronal structure, synaptic plasticity, and behavior
During central nervous system development, extracellular matrix (ECM) receptors and their ligands play key roles as guidance molecules, informing neurons where and when to send axonal and dendritic projections, establish connections, and form synapses between pre- and postsynaptic cells. Once stable synapses are formed, many ECM receptors transition in function to control the maintenance of stable connections between neurons and regulate synaptic plasticity.
